Systems and Methods for Electrical Stimulation of Biological Systems

ABSTRACT

Systems and methods for the treatment of gastroesophageal reflux disease (GERD) include at least one electrically stimulating electrode coupled to a pulse generator. Individuals with GERD are treated by implanting a stimulation device within and/or proximate the patient&#39;s lower esophageal sphincter, gastric fundus, or other nearby gastrointestinal structures and applying electrical stimulation to the patient&#39;s lower esophageal sphincter and/or fundus, in accordance with certain predefined protocols. Electrical stimulation provided by the disclosed systems results in an increase in the length of the high pressure zone of the LES and/or modulation of the receptive relaxation response of the fundus to decrease gastric pressure, creating a longer barrier to the reflux of gastric contents or increasing functional lower esophageal pressure respectively, thereby treating GERD.

CROSS-REFERENCE

The present application is a continuation application of U.S. patentapplication Ser. No. 16/528,997, entitled “Systems and Methods forElectrical Stimulation of Biological Systems” and filed on Aug. 1, 2019,which is a continuation application of U.S. patent application Ser. No.15/639,590, of the same title, filed on Jun. 30, 2017, and issued asU.S. Pat. No. 10,406,356, which is a continuation application of U.S.patent application Ser. No. 14/548,793, of the same title, filed on Nov.20, 2014, and issued as U.S. Pat. No. 9,724,510 on Aug. 8, 2017, whichrelies on U.S. Provisional Patent Application No. 61/906,812, entitled“Systems and Methods for Increasing the Length of the Lower EsophagealSphincter High Pressure Zone” and filed on Nov. 20, 2013 and U.S.Provisional Patent Application No. 61/906,815, entitled “Systems andMethods for Modulating the Receptive Relaxation of the Fundus” and filedon Nov. 20, 2013, for priority.

U.S. patent application Ser. No. 14/548,793 is also acontinuation-in-part application of U.S. patent application Ser. No.14/500,856, entitled “Device and Implantation System for ElectricalStimulation of Biological Systems” filed on Sep. 29, 2014, and issued asU.S. Pat. No. 9,561,367 on Feb. 7, 2017, which is a continuationapplication of U.S. patent application Ser. No. 14/201,766, (“'766application”) of the same title, filed on Mar. 7, 2014, and issued asU.S. Pat. No. 9,345,879 on May 24, 2016, which is a continuation-in-partapplication of U.S. patent application Ser. No. 14/175,927, of the sametitle and filed on Feb. 7, 2014, which is a continuation-in-partapplication of U.S. patent application Ser. No. 13/661,483, entitled“Methods and Systems for Treating the Gastrointestinal Tract” and filedon Oct. 26, 2012, which is a continuation of U.S. patent applicationSer. No. 12/775,436, entitled “Method and Apparatus for Treatment of theGastrointestinal Tract” and filed on May 6, 2010, which is acontinuation application of U.S. patent application Ser. No. 11/539,645,of the same title, filed on Oct. 9, 2006, and issued as U.S. Pat. No.7,738,961 on Jun. 15, 2010.

The '766 application is also a continuation-in-part application of U.S.patent application Ser. No. 13/041,063, entitled “Device andImplantation System for Electrical Stimulation of Biological Systems”,filed on Mar. 4, 2011, and issued as U.S. Pat. No. 8,712,529 on Apr. 29,2014, which relies on U.S. Provisional Patent Application No.61/444,849, of the same title and filed on Feb. 21, 2011; 61/422,967,entitled “Methods and Systems for Improving the Operation of An ActiveImplantable Medical Device” and filed on Dec. 14, 2010; 61/414,378,entitled “Method and System for Implanting a Medical Device Into A HumanBody and Electrically Stimulating Human Tissue”, filed on Nov. 16, 2010;61/384,105, entitled “Device and Implantation System for ElectricalStimulation of Biological Tissues” and filed on Sep. 17, 2010;61/371,146, of the same title and filed on Aug. 5, 2010; 61/328,702, ofthe same title and filed on Apr. 28, 2010; 61/318,843, of the same titleand filed on Mar. 30, 2010; and 61/310,755, of the same title and filedon Mar. 5, 2010, for priority.

The '766 application is also a continuation-in-part application of U.S.patent application Ser. No. 13/041,114, entitled “Device andImplantation System for Electrical Stimulation of Biological Systems”,filed on Mar. 4, 2011, and issued as U.S. Pat. No. 8,712,530 on Apr. 29,2014, which relies on U.S. Provisional Patent Application No.61/444,849, of the same title and filed on Feb. 21, 2011; 61/422,967,entitled “Methods and Systems for Improving the Operation of An ActiveImplantable Medical Device” and filed on Dec. 14, 2010; 61/414,378,entitled “Method and System for Implanting a Medical Device Into A HumanBody and Electrically Stimulating Human Tissue”, filed on Nov. 16, 2010;61/384,105, entitled “Device and Implantation System for ElectricalStimulation of Biological Tissues” and filed on Sep. 17, 2010;61/371,146, of the same title and filed on Aug. 5, 2010; 61/328,702, ofthe same title and filed on Apr. 28, 2010; 61/318,843, of the same titleand filed on Mar. 30, 2010; and 61/310,755, of the same title and filedon Mar. 5, 2010, for priority.

The '766 application is also a continuation-in-part application of U.S.patent application Ser. No. 13/934,040, entitled “Device andImplantation System for Electrical Stimulation of Biological Systems”,filed on Jul. 2, 2013, and issued as U.S. Pat. No. 8,798,753 on Aug. 5,2014, which is a continuation application of U.S. patent applicationSer. No. 12/359,317, of the same title, filed on Jan. 25, 2009, andissued as United U.S. Pat. No. 8,543,210 on Sep. 24, 2013, which relieson U.S. Provisional Patent Application No. 61/023,535, entitled “Devicefor Electrical Stimulation of Biological Systems” and filed on Jan. 25,2008, for priority.

The '766 application is also related to U.S. patent application Ser. No.13/041,098, entitled “Device and Implantation System for ElectricalStimulation of Biological Systems”, filed on Mar. 4, 2011, and nowissued as U.S. Pat. No. 8,447,403.

The '766 specification is also related to U.S. patent application Ser.No. 13/041,116, entitled “Device and Implantation System for ElectricalStimulation of Biological Systems”, filed on Mar. 4, 2011, and nowissued as U.S. Pat. No. 8,447,404.

Each of the above applications is hereby incorporated by reference inits entirety.

FIELD

The present specification relates generally to electrical stimulation ofanatomical structures to treat biological conditions. More particularly,the present specification relates to electrical stimulation of theesophagus and/or stomach to increase the length of the lower esophagealsphincter (LES) high pressure zone and/or increase the receptiverelaxation response of the fundus of the stomach for the treatment ofgastroesophageal reflux disease (GERD).

BACKGROUND

Electrical stimulation of nerves and surrounding tissue is used to treata variety of conditions. For example, electrical stimulation can be usedto restore partial function to limbs or organs following traumaticinjury. Electrical stimulation can also be used to reduce pain.Specifically, electrical stimulation can be used to treat disordersassociated with the gastrointestinal (GI) system, such as, obesity andgastroesophageal reflux disease (GERD).

Gastro-esophageal reflux disease (GERD) is a common health problem andis expensive to manage in both primary and secondary care settings. Thiscondition results from exposure of esophageal mucosa to gastric acid andbile as the gastro-duodenal content refluxes from the stomach into theesophagus. The acid and bile damages the esophageal mucosa resulting inheartburn, ulcers, bleeding, and scarring, and long term complicationssuch as Barrett's esophagus (pre-cancerous esophageal lining) andadeno-cancer of the esophagus. Patients with GERD may only experiencesymptoms during the day, referred to as diurnal GERD, and may notexperience any GERD symptoms at night, referred to as nocturnal GERD.Diurnal or daytime or upright GERD has been associated with tLESR, andmay be diagnosed where a patient has symptoms of heartburn,regurgitation or both.

The severity of GERD increases progressively from postprandial toupright, to supine, to bipositional reflux. A structural defect asreflected by decreased LES pressure and length is also significantlyless common with postprandial and upright reflux. The improvedesophageal sensation associated with improved saliva production thatneutralizes the refluxed acid and increased clearance of the refluxateaided by gravity results in lesser esophageal damage.

Lifestyle advice and antacid therapy are advocated as first linetreatments for the disease. However, since most patients with moderateto severe cases of GERD do not respond adequately to these first-linemeasures and need further treatment, other alternatives, includingpharmacological, endoscopic, and surgical treatments are employed.

The most commonly employed pharmacological treatment is daily use of H2receptor antagonists (H2RAs) or proton-pump inhibitors (PPIs) for acidsuppression. Since gastro-esophageal reflux disease usually relapsesonce drug therapy is discontinued, most patients with the disease,therefore, need long-term drug therapy. However, daily use of PPIs orH2RAs is not universally effective in the relief of GERD symptoms or asmaintenance therapy. Additionally, not all patients are comfortable withthe concept of having to take daily or intermittent medication for therest of their lives and many are interested in nonpharmacologicaloptions for managing their reflux disease.

Several endoscopic procedures for the treatment of GERD have been tried.These procedures can be divided into three approaches: endoscopicsuturing, wherein stitches are inserted in the gastric cardia to plicateand strengthen the lower esophageal sphincter; endoscopic application ofenergy to the lower esophagus; and, injection of bulking agents into themuscle layer of the distal esophagus. These procedures, however, are notwithout their risks, besides being technically demanding and involving along procedure time. As a result, these procedures have largely beendiscontinued.

Open surgical or laparoscopic fundoplication is also used to correct thecause of the disease. However, surgical procedures are associated withsignificant morbidity and small but not insignificant mortality rates.Moreover, long-term follow-up with patients treated by surgery suggeststhat many patients continue to need acid suppressive medication. Thereis also no convincing evidence that fundoplication reduces the risk ofesophageal adenocarcinoma in the long term.

Electrical stimulation is one methodology aimed at treating GERD.Electrical stimulation employs an implantable, pacemaker-like device todeliver low-level electrical stimulation to portions of the esophagusand/or stomach. For example, in U.S. Pat. No. 6,901,295, assigned to theapplicant of the current invention, “A method and apparatus forelectrical stimulation of the lower esophageal sphincter (LES) isprovided. Electrode sets are placed in the esophagus in an arrangementthat induce contractions of the LES by electrical stimulation of thesurrounding tissue and nerves. The electrical stimulus is applied by apulse generator for periods of varying duration and varying frequency soas to produce the desired contractions. The treatment may be short-termor may continue throughout the life of the patient in order to achievethe desired therapeutic effect. The stimulating electrode sets can beused either alone or in conjunction with electrodes that senseesophageal peristalsis. The electrode sets can be placed endoscopically,surgically or radiologically.” The referenced invention relies onsensing certain physiological changes in the esophagus, such as changesin esophageal pH, to detect acid reflux. Once a change in esophageal pHis recognized, the system generates an electrical stimulation in anattempt to instantaneously close the LES and abort the episode of acidreflux. U.S. Pat. No. 6,901,295 is hereby incorporated by reference inits entirety.

While current electrical stimulation systems are effective in treatingGERD, they do not address all of the anatomical factors involved in thecause of the disease. Particularly, patients suffering from GERD oftenexhibit a shortened LES high pressure zone. The LES high pressure zoneis a segment of the LES in which the pressure is higher than thepressure in the immediately proximal and distal portions of theesophagus. The higher pressure in this zone helps to keep stomachcontents from refluxing. A shortened zone presents less resistance torefluxing gastric acid. Lengthening the LES high pressure zone wouldcreate a longer barrier to refluxing stomach contents. Therefore, whatis needed is an electrical stimulation system which acts to increase thelength of the LES high pressure zone, thereby reducing the frequency andseverity of GERD.

SUMMARY

The present specification discloses a system for increasing the lengthof a high pressure zone of a lower esophageal sphincter (LES) of apatient, said system comprising: at least one electrically stimulatingelectrode positioned proximate said LES; a waveform generator coupled tosaid at least one electrode; and, a controller configured toelectrically stimulate an area proximate said LES to increase the lengthof said high pressure zone above a threshold level which reduces atleast one of a frequency of occurrence or an intensity ofgastroesophageal reflux symptoms in said patient.

In one embodiment, the at least one electrode is positioned within saidLES. In another embodiment, the at least one electrode is positionedwithin a gastric cardia of said patient. In another embodiment, the atleast one electrode is positioned in an area within 3 cm of said LES.

In one embodiment, the system comprises at least two electrodes whereinat least one first electrode is positioned within said LES and at leastone second electrode is positioned within a gastric cardia of saidpatient. In another embodiment, the system comprises at least twoelectrodes wherein at least one first electrode is positioned withinsaid LES and at least one second electrode is positioned in an areawithin 3 cm of said LES. In another embodiment, the system comprises atleast two electrodes wherein at least one first electrode is positionedwithin a gastric cardia of said patient and at least one secondelectrode is positioned in an area within 3 cm of said LES.

In one embodiment, the system comprises at least three electrodeswherein at least one first electrode is positioned within said LES, atleast one second electrode is positioned within a gastric cardia of saidpatient, and at least one third electrode is positioned in an areawithin 3 cm of said LES.

In one embodiment, the high pressure zone has a baseline length, definedas the length of the high pressure zone prior to stimulation, and thethreshold level defines a length of the high pressure zone which is atleast 10% greater than said baseline length.

In various embodiments, the controller causes the waveform generator togenerate a pulse stream defined by a plurality of parameters comprising:a pulse width having a range of 30 μsec to 5 msec; a pulse amplitudehaving a range of 2 to 15 mAmp; an on period ranging from 1 second to 23hours, 59 minutes, and 59 seconds; an off period ranging from 1 secondto 23 hours, 59 minutes, and 59 seconds; a duty cycle ranging from 1 to100%; and, a pulse frequency. In various embodiments, the pulsefrequency has a range of 1-100 Hz or 1-59 cpm.

The present specification also discloses a system for increasing thelength of a high pressure zone of a lower esophageal sphincter (LES) ofa patient, said system comprising: at least one electrically stimulatingelectrode positioned proximate said LES; a waveform generator coupled tosaid at least one electrode; a controller configured to electricallystimulate an area proximate said LES to increase the length of said highpressure zone above a threshold level which reduces at least one of afrequency of occurrence or an intensity of gastroesophageal refluxsymptoms in said patient; wherein an average pressure within said highpressure zone is greater than 5 mm Hg and wherein said high pressurezone has a baseline length prior to stimulation and said threshold leveldefines a length of said high pressure zone which is at least 10%greater than said baseline length.

In one embodiment, the said at least one electrode is positioned withinsaid LES. In another embodiment, the at least one electrode ispositioned within a gastric cardia of said patient or within 3 cm ofsaid LES.

In one embodiment, the system further comprises at least one sensor forsensing at least one physiological parameter of said patient.

In one embodiment, the said at least one sensor is configured to measureany one or combination of LES high pressure zone length, LES pressure,esophageal pH, inclinometer data, temperature, or accelerometer data.

In one embodiment, the controller is configured to electricallystimulate said area proximate said LES based on data sensed by said atleast one sensor.

In various embodiments, the controller causes the waveform generator togenerate a pulse stream defined by a plurality of parameters comprising:a pulse width having a range of 30 μsec to 5 msec; a pulse amplitudehaving a range of 2 to 15 mAmp; an on period ranging from 1 second to 23hours, 59 minutes, and 59 seconds; an off period ranging from 1 secondto 23 hours, 59 minutes, and 59 seconds; a duty cycle ranging from 1 to100%; and, a pulse frequency. In various embodiments, the pulsefrequency has a range of 1-100 Hz or 1-59 cpm.

The present specification also discloses a method for increasing thelength of a high pressure zone of a lower esophageal sphincter (LES) ofa patient, said method comprising the steps of: providing an electricalstimulation system, said system comprising: at least one electricallystimulating electrode; a waveform generator coupled to said at least oneelectrode; and, a controller configured to operate said waveformgenerator to transmit an electrical current to said at least oneelectrode; implanting said at least one electrode within 3 cm of saidLES or within a gastric cardia of said patient; and, operating saidcontroller to cause said at least one electrode to electricallystimulate an area proximate said LES to increase the length of said highpressure zone above a threshold level which reduces at least one of afrequency of occurrence or an intensity of gastroesophageal refluxsymptoms in said patient.

In one embodiment, referring to the method described above, the at leastone electrode is positioned within said LES.

In one embodiment, referring to the method described above, an averagepressure within said high pressure zone is greater than 5 mm Hg.

In one embodiment, referring to the method described above, the highpressure zone has a baseline length prior to stimulation and saidthreshold level defines a length of said high pressure zone which is atleast 10% greater than said baseline length.

In one embodiment, referring to the method described above, theelectrical stimulation system further comprises at least one sensor andthe method further comprises the steps of: sensing at least onephysiological parameter of said patient via said at least one sensor;and, modifying the operation of said controller to cause said at leastone electrode to electrically stimulate an area proximate said LES basedupon said at least one sensed physiological parameter.

In various embodiments, referring to the method described above, thecontroller causes the waveform generator to generate a pulse streamdefined by a plurality of parameters comprising: a pulse width having arange of 30 μsec to 5 msec; a pulse amplitude having a range of 2 to 15mAmp; an on period ranging from 1 second to 23 hours, 59 minutes, and 59seconds; an off period ranging from 1 second to 23 hours, 59 minutes,and 59 seconds; a duty cycle ranging from 1 to 100%; and, a pulsefrequency. In various embodiments, the pulse frequency has a range of1-100 Hz or 1-59 cpm.

The present specification also discloses a system for modulating muscletone of a gastric fundus and decreasing gastric pressure of a patient.There exists an effective, or functional, LES pressure which is agradient between the actual LES pressure and the gastric pressure.Current electrical stimulation systems treat GERD by causing an increasein the actual LES pressure and therefore an increase in the functionalLES pressure. However, functional LES pressure can also be increased bydecreasing the gastric pressure. A normal human stomach includes areceptive relaxation response in the fundus, or upper portion, inresponse to food intake. The stomach is under neural control to maintaina constant pressure as a person eats. The muscles of the stomach relaxduring food accumulation so that the stomach can expand and pressure canremain constant. As such, the mechanical changes that occur in the wallsof the fundus during this relaxation response can be considered aparameter in controlling post-prandial reflux. Therefore, what is neededis an electrical stimulation system to treat GERD which functions byproviding stimulation in and/or proximate the fundus, thereby enhancingthe normal receptive relaxation response and decreasing gastricpressure. The decreased gastric pressure results in an increasedfunctional LES pressure and reduces the likelihood of a reflux event.

Accordingly, the present application discloses a system for modulatingmuscle tone of a gastric fundus and decreasing gastric pressure of apatient that comprises at least one electrically stimulating electrodepositioned proximate said gastric fundus; a waveform generator coupledto said at least one electrode; and, a controller configured toelectrically stimulate an area proximate said gastric fundus to decreasesaid gastric pressure below a threshold level which reduces at least oneof a frequency of occurrence or an intensity of gastroesophageal refluxsymptoms in said patient.

In one embodiment, the at least one electrode is positioned within saidgastric fundus. In another embodiment, the at least one electrode ispositioned within a lower esophageal sphincter (LES) of said patient. Inanother embodiment, the at least one electrode is positioned in an areawithin 3 cm of a lower esophageal sphincter (LES) of said patient.

In one embodiment, the system comprises at least two electrodes whereinat least one first electrode is positioned within said gastric fundusand at least one second electrode is positioned within a loweresophageal sphincter (LES) of said patient. In another embodiment, thesystem comprises at least two electrodes wherein at least one firstelectrode is positioned within said gastric fundus and at least onesecond electrode is positioned in an area within 3 cm of a loweresophageal sphincter (LES) of said patient. In another embodiment, thesystem comprises at least two electrodes wherein at least one firstelectrode is positioned within a lower esophageal sphincter (LES) ofsaid patient and at least one second electrode is positioned in an areawithin 3 cm of said LES.

In one embodiment, the system comprises at least three electrodeswherein at least one first electrode is positioned within said gastricfundus, at least one second electrode is positioned within a loweresophageal sphincter (LES) of said patient, and at least one thirdelectrode is positioned in an area within 3 cm of said LES.

In one embodiment, gastric pressure is equal to a baseline pressureprior to stimulation and said threshold level defines a gastric pressurewhich is at least 10% less than said baseline pressure.

In various embodiments, the controller causes the waveform generator togenerate a pulse stream defined by a plurality of parameters comprising:a pulse width having a range of 30 μsec to 5 msec; a pulse amplitudehaving a range of 2 to 15 mAmp; an on period ranging from 1 second to 23hours, 59 minutes, and 59 seconds; an off period ranging from 1 secondto 23 hours, 59 minutes, and 59 seconds; a duty cycle ranging from 1 to100%; and, a pulse frequency. In various embodiments, the pulsefrequency has a range of 1-100 Hz or 1-59 cpm.

The present specification also discloses a system for modulating muscletone of a gastric fundus and decreasing gastric pressure of a patient,said system comprising: at least one electrically stimulating electrodepositioned proximate said gastric fundus; a waveform generator coupledto said at least one electrode; a controller configured to electricallystimulate an area proximate said gastric fundus to decrease said gastricpressure below a threshold level which reduces at least one of afrequency of occurrence or an intensity of gastroesophageal refluxsymptoms in said patient; wherein said gastric pressure includes abaseline pressure prior to stimulation which is equal to approximately10 mm Hg and said threshold level defines a gastric pressure which is atleast 10% less than said baseline pressure.

In one embodiment, the at least one electrode is positioned within saidgastric fundus. In another embodiment, the at least one electrode ispositioned within a lower esophageal sphincter (LES) of said patient orwithin 3 cm of said LES.

In one embodiment, the system further comprises at least one sensor forsensing at least one physiological parameter of said patient.

In one embodiment, the at least one sensor is configured to measure anyone or combination of gastric pressure, LES pressure, esophageal pH,inclinometer data, temperature, or accelerometer data.

In one embodiment, the controller is configured to electricallystimulate said area proximate said gastric fundus based on data sensedby said at least one sensor.

In various embodiments, the controller causes the waveform generator togenerate a pulse stream defined by a plurality of parameters comprising:a pulse width having a range of 30 μsec to 5 msec; a pulse amplitudehaving a range of 2 to 15 mAmp; an on period ranging from 1 second to 23hours, 59 minutes, and 59 seconds; an off period ranging from 1 secondto 23 hours, 59 minutes, and 59 seconds; a duty cycle ranging from 1 to100%; and, a pulse frequency. In various embodiments, the pulsefrequency has a range of 1-100 Hz or 1-59 cpm.

The present specification also discloses a method for modulating muscletone of a gastric fundus and decreasing gastric pressure of a patient,said method comprising the steps of: providing an electrical stimulationsystem, said system comprising: at least one electrically stimulatingelectrode; a waveform generator coupled to said at least one electrode;and, a controller configured to operate said waveform generator totransmit an electrical current to said at least one electrode;implanting said at least one electrode in a gastric fundus or within 3cm of a lower esophageal sphincter (LES) of said patient; and, operatingsaid controller to cause said at least one electrode to electricallystimulate an area proximate said gastric fundus to decrease said gastricpressure below a threshold level which reduces at least one of afrequency of occurrence or an intensity of gastroesophageal refluxsymptoms in said patient.

In one embodiment, referring to the method described above, an averagegastric pressure prior to stimulation is equal to approximately 10 mmHg.

In one embodiment, referring to the method described above, the at leastone electrode is positioned within said LES.

In one embodiment, referring to the method described above, gastricpressure is equal to a baseline pressure prior to stimulation and saidthreshold level defines a gastric pressure which is at least 10% lessthan said baseline pressure.

In one embodiment, referring to the method described above, theelectrical stimulation system further comprises at least one sensor andthe method further comprises the steps of: sensing at least onephysiological parameter of said patient via said at least one sensor;and, modifying the operation of said controller to cause said at leastone electrode to electrically stimulate an area proximate said gastricfundus based upon said at least one sensed physiological parameter.

In various embodiments, referring to the method described above, thecontroller causes the waveform generator to generate a pulse streamdefined by a plurality of parameters comprising: a pulse width having arange of 30 μsec to 5 msec; a pulse amplitude having a range of 2 to 15mAmp; an on period ranging from 1 second to 23 hours, 59 minutes, and 59seconds; an off period ranging from 1 second to 23 hours, 59 minutes,and 59 seconds; a duty cycle ranging from 1 to 100%; and, a pulsefrequency. In various embodiments, the pulse frequency has a range of1-100 Hz or 1-59 cpm.

The aforementioned and other embodiments of the present invention shallbe described in greater depth in the drawings and detailed descriptionprovided below.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other features and advantages of the present invention will befurther appreciated, as they become better understood by reference tothe detailed description when considered in connection with theaccompanying drawings:

FIG. 1 is a graph depicting the physiology, including pressuremeasurements, of a normal swallow;

FIG. 2A is a graph depicting a wet swallow at baseline for a GERDpatient;

FIG. 2B is a graph depicting one embodiment of an improved wet swallowwith stimulation;

FIG. 2C is a flow chart illustrating the steps involved in oneembodiment of a method of treating a patient with GERD by decreasinggastric pressure through electrical stimulation;

FIG. 3A is an illustration of the distal portion of an esophagus of apatient with gastroesophageal reflux disease (GERD);

FIG. 3B is an illustration of the distal portion of an esophagusreceiving stimulation targeted at increasing the length of the LES highpressure zone, in accordance with one embodiment of the presentspecification;

FIG. 3C is a flow chart illustrating the steps involved in oneembodiment of a method of treating a patient with GERD by increasing thelength of the LES high pressure zone through electrical stimulation;

FIG. 4 is a graph depicting one exemplary pressure profile, both duringstimulation and post-stimulation;

FIG. 5 is a graph depicting another exemplary pressure profile, bothduring stimulation and post-stimulation;

FIG. 6 is a graph depicting another exemplary pressure profile, bothduring stimulation and post-stimulation;

FIG. 7 is a graph depicting yet another exemplary pressure profile, bothduring stimulation and post-stimulation;

FIG. 8 is a schematic of modulated pulse trains in accordance with oneembodiment of the present specification;

FIG. 9 is an illustration of a one embodiment of a timeline depicting astimulation session followed by a supine refractory time period;

FIG. 10 is an illustration of one embodiment of a timeline depicting astimulation session triggered by supine stimulation mode followed by asupine cancel period;

FIG. 11 is an illustration depicting one exemplary electrodeconfiguration in the esophagus of a patient;

FIG. 12 is an illustration depicting another exemplary electrodeconfiguration in the esophagus of a patient;

FIG. 13A is an illustration depicting another exemplary electrodeconfiguration in the esophagus of a patient;

FIG. 13B is an illustration of the distal portion of an esophagus of apatient depicting a first pair of electrodes implanted in the LES and asecond pair of electrodes implanted in the gastric cardia, in accordancewith one embodiment of the present specification;

FIG. 13C is an illustration of the distal portion of an esophagus of apatient depicting a first pair of electrodes implanted in the LES and asecond pair of electrodes implanted proximate the LES, in accordancewith one embodiment of the present specification;

FIG. 13D is an illustration of the distal portion of an esophagus of apatient depicting a pair of electrodes implanted in the gastric cardia,in accordance with one embodiment of the present specification;

FIG. 13E is an illustration of the distal portion of an esophagus of apatient depicting a pair of electrodes implanted proximate the LES, inaccordance with one embodiment of the present specification;

FIG. 13F is an illustration of the distal portion of an esophagus of apatient depicting a first pair of electrodes implanted in the gastriccardia and a second pair of electrodes implanted proximate the LES, inaccordance with one embodiment of the present specification;

FIG. 13G is an illustration of the distal portion of an esophagus of apatient depicting a first pair of electrodes implanted in the LES, asecond pair of electrodes implanted in the gastric cardia, and a thirdpair of electrodes implanted proximate the LES, in accordance with oneembodiment of the present specification;

FIG. 13H is an illustration of the distal portion of an esophagus of apatient depicting a first pair of electrodes implanted in the LES and asecond pair of electrodes implanted in the gastric fundus, in accordancewith one embodiment of the present specification;

FIG. 13I is an illustration of the distal portion of an esophagus of apatient depicting a first pair of electrodes implanted in the LES and asecond pair of electrodes implanted proximate the LES, in accordancewith one embodiment of the present specification;

FIG. 13J is an illustration of the distal portion of an esophagus of apatient depicting a pair of electrodes implanted in the gastric fundus,in accordance with one embodiment of the present specification;

FIG. 13K is an illustration of the distal portion of an esophagus of apatient depicting a pair of electrodes implanted proximate the LES, inaccordance with one embodiment of the present specification;

FIG. 13L is an illustration of the distal portion of an esophagus of apatient depicting a first pair of electrodes implanted in the gastricfundus and a second pair of electrodes implanted proximate the LES, inaccordance with one embodiment of the present specification;

FIG. 13M is an illustration of the distal portion of an esophagus of apatient depicting a first pair of electrodes implanted in the LES, asecond pair of electrodes implanted in the gastric fundus, and a thirdpair of electrodes implanted proximate the LES, in accordance with oneembodiment of the present specification;

FIG. 14 is a cross-sectional illustration of the upper gastrointestinaltract showing a pH sensing capsule in the esophagus and a stimulatoradapted to be implanted within the tissue of the patient;

FIG. 15 is a flow chart depicting a certain parameter setting method ofone embodiment of the present specification;

FIG. 16 is a block diagram depicting the modules of an exemplaryembodiment of the stimulating device of the present specification;

FIG. 17 is a block diagram depicting the modules of another exemplaryembodiment of the stimulating device of the present specification;

FIG. 18 is a block diagram depicting the modules of another exemplaryembodiment of the stimulating device of the present specification;

FIG. 19 is a block diagram depicting the modules of another exemplaryembodiment of the stimulating device of the present specification;

FIG. 20 is a block diagram depicting the modules of another exemplaryembodiment of the stimulating device of the present specification;

FIG. 21 is a block diagram depicting the modules of another exemplaryembodiment of the stimulating device of the present specification;

FIG. 22 is a block diagram depicting the modules of another exemplaryembodiment of the stimulating device of the present specification;

FIG. 23 is a block diagram depicting the modules of yet anotherexemplary embodiment of the stimulating device of the presentspecification;

FIG. 24 is a graph relating pressure increases to baseline, stimulation,and post-stimulation periods, in accordance with one embodiment of thepresent specification;

FIG. 25 is a graph showing an improved LES pressure profile over time,in accordance with one embodiment of the present specification;

FIG. 26 is another graph showing an improved LES pressure profile overtime, in accordance with one embodiment of the present specification;

FIG. 27 is a graph showing LES pressures pre-stimulation, in accordancewith one embodiment of the present specification;

FIG. 28 is a graph showing LES pressures during stimulation, inaccordance with one embodiment of the present specification;

FIG. 29 is a graph showing LES pressures post-stimulation, in accordancewith one embodiment of the present specification; and

FIG. 30 is another graph showing an improved LES pressure profile overtime.

DETAILED DESCRIPTION

The present specification discloses programmable implantableelectro-medical devices for the treatment of gastro-esophageal refluxdisease (GERD). The present specification discloses systems and methodsfor treating gastroesophageal reflux disease (GERD) in a patient byelectrically stimulating a portion of the lower esophagus and/or stomachto cause an increase in the length of the high pressure zone of thelower esophageal sphincter (LES). In one embodiment, the systems andmethods of the present specification increase the length of the highpressure zone of the LES without changing the manometric maximumpressure in the region of the LES. In other words, the stimulationprovided by the systems enhances the length of the high pressure zonebut does not change overall pressure.

In one embodiment, the systems for increasing the length of the LES highpressure zone provide electrical stimulation in the LES. In anotherembodiment, the systems provide electrical stimulation to the gastriccardia. In another embodiment, the systems provide electricalstimulation both in the LES and to the gastric cardia. In anotherembodiment, the systems provide electrical stimulation to an areaproximate the LES. In one embodiment, the area proximate the LES iswithin 3 cm of the LES. In another embodiment, the systems provideelectrical stimulation both in the LES and to an area proximate the LES.In another embodiment, the systems provide electrical stimulation toboth the gastric cardia and an area proximate the LES. In yet anotherembodiment, the systems provide electrical stimulation in the LES, tothe gastric cardia, and to an area proximate the LES. In otherembodiments, the systems for increasing the length of the LES highpressure zone provide electrical stimulation to other gastrointestinalstructures, including but not limited to, any portion of the stomach.

With regards to the present specification, the high pressure zone of thelower esophageal sphincter (LES) is defined as a portion of theesophagus proximate the LES of a patient wherein the intra-esophagealpressure measures greater than the intra-esophageal pressure of theesophagus immediately proximal and distal to said portion. Pressuresaveraging over 5 mm Hg are considered to be in the high pressure zone.The average length of the LES is approximately 3 to 5 cm and includes ahigh pressure zone that is typically greater than 1 cm in length (forexample, 1 to 5 cm). In a patient suffering from GERD, this highpressure zone is typically shortened. The systems of the presentspecification targeted at increasing the length of the LES high pressurezone enhance said high pressure zone in diseased patients by increasingits length while not necessarily increasing the overall maximum pressurewithin the zone. In one embodiment, the systems targeted at increasingthe length of the LES high pressure zone increase the length of saidhigh pressure zone of the LES by at least 10% compared to a baselinelength before stimulation. For example, a patient has an LES with a highpressure zone measuring 2 cm in length wherein the pressure is over 5 mmHg with a maximum of 10 mm Hg. Using various systems and methods of thepresent specification, the length of the LES having a pressure greaterthan 5 cm is increased to 3 cm while the maximum pressure remains at 10mm Hg. Therefore, the length of the high pressure zone has been enhancedwhile the overall pressure remains unchanged.

Electrical stimulation of the anatomical structures proximate the LESresults in activation of additional muscle fibers proximal and distal tothe high pressure zone, causing these muscles to contract and therebynarrow the lumen of the esophagus. Pressure increases above 5 mm Hg inthese constricted portions of the esophagus, resulting in an increase inthe length of the high pressure zone. As such, various systems andmethods of the present specification act to treat GERD by creating alonger barrier (longer high pressure zone) in the esophagus to preventthe reflux of acidic gastric contents.

The present specification also discloses systems and methods fortreating gastroesophageal reflux disease (GERD) in a patient byelectrically stimulating a portion of the lower esophagus and/or stomachto cause an increase in the receptive relaxation response of the fundusof the stomach. The increase in the relaxation response of the fundusleads to mechanical changes in the wall of the fundus, resulting in anincrease in gastric size and volume and a decrease in gastric pressure.The decrease in gastric pressure translates to an increase in functionallower esophageal sphincter (LES) pressure, where functional LES pressureis defined as the relationship between actual LES pressure and actualgastric pressure, or a gastroesophageal pressure gradient. The increasein functional LES pressure treats GERD by creating a stronger barrier atthe gastroesophageal junction (GEJ), preventing the reflux of gastriccontents into the esophagus.

In one embodiment, the systems for increasing the relaxation response ofthe fundus provide electrical stimulation in the LES. In anotherembodiment, the systems provide electrical stimulation to the fundus ofthe stomach. In another embodiment, the systems provide electricalstimulation both in the LES and to the fundus. In another embodiment,the systems provide electrical stimulation to an area proximate the LES.In one embodiment, the area proximate the LES is within 3 cm of the LES.In another embodiment, the systems provide electrical stimulation bothin the LES and to an area proximate the LES. In another embodiment, thesystems provide electrical stimulation to both the fundus and an areaproximate the LES. In yet another embodiment, the systems provideelectrical stimulation in the LES, to the fundus, and to an areaproximate the LES. In other embodiments, the systems for increasing therelaxation response of the fundus provide electrical stimulation toother gastrointestinal structures, including but not limited to, anyportion of the stomach.

Providing electrical stimulation to the anatomical areas in and aroundthe fundus of the stomach to enhance receptive relaxation can have anumber of beneficial effects upon the gastrointestinal tract withregards to acid reflux. For example, in one embodiment, stimulationproduces changes in post-prandial gastric geometry. These changes ingeometry include an increase in gastric size and volume resulting in adecrease in gastric pressure. Normal gastric pressure averagesapproximately 10 mm Hg, which varies with breathing. In one embodiment,the systems and methods of the present specification targeted atincreasing the relaxation response of the fundus cause a decrease inaverage gastric pressure to below 10 mm Hg. In one embodiment, thesystems and methods targeted at increasing the relaxation response ofthe fundus cause a decrease in average gastric pressure by at least 10%compared to a baseline gastric pressure before stimulation. Thefunctional LES pressure, as described above, is a pressure gradientrelating the actual LES pressure to the actual gastric pressure. As theactual gastric pressure decreases, the functional LES pressure increaseswhile the actual LES pressure remains the same. An increase infunctional LES pressure results in fewer reflux events as the gastriccontents must travel against a greater pressure gradient to enter backinto the esophagus. In one embodiment, the systems and methods targetedat increasing the relaxation response of the fundus cause an increase inthe functional LES pressure by at least 10%.

In one embodiment, electrical stimulation is applied after a patienteats to provide relief from post-prandial reflux. In this embodiment,the electrical stimulation enhances the receptive relaxation alreadyoccurring as a result of the contact of ingested food with stretchreceptors on the stomach wall. In one embodiment, electrical stimulationis applied during fasting and during sleep times. Gastric wallrelaxation in this embodiment occurs only as a result of the electricalstimulation and helps prevent reflux events not associated with eating.In one embodiment, a diabetic patient receives electrical stimulation inaccordance with the systems and methods of the present specification. Inthis embodiment, the electrical stimulation acts to restore thereceptive relaxation of the fundus which has become deficient in thediabetic patient.

In one embodiment, modulating (reducing) the tone of the fundus throughelectrical stimulation provided by the systems and methods of thepresent specification reduces the number of transient lower esophagealsphincter relaxation (tLESR) events. In one embodiment, the systems andmethods of the present specification targeted at increasing therelaxation response of the fundus reduce the number of tLESR events byat least 10%. In another embodiment, modulating (reducing) the tone ofthe fundus through electrical stimulation provided by the systems andmethods of the present specification does not affect the number of tLESRevents but rather reduces the likelihood that reflux will occur during atLESR event. This occurs as a result of decreasing gastric pressure andincreasing functional LES pressure. Although the LES relaxes and actualLES pressure decreases for a short period of time, the decrease ingastric pressure resulting from the reduction in gastric tone asprovided by said systems is great enough to prevent reflux. In otherwords, in one embodiment, the decrease in actual gastric pressure isgreater than the decrease in actual LES pressure such that functionalLES pressure is still increased, thereby preventing reflux. In oneembodiment, the systems and methods targeted at increasing therelaxation response of the fundus reduce the likelihood of reflux duringa tLESR event by at least 10%. In another embodiment, modulating(reducing) the tone of the fundus through electrical stimulationprovided by the systems and methods of the present specification reducesthe number of tLESR events and reduces the likelihood that reflux willoccur during a tLESR event.

In one embodiment, the systems and methods of the present specificationtargeted at increasing the relaxation response of the fundus modulateacid pocket geometry within the gastroesophageal junction (GEJ). Acidpockets form within the GEJ of patients having GERD. Acid pockets formin a patient with GERD as the pressure gradient at the GEJ approacheszero. Approximately equal LES pressure and gastric pressure push againstone another at the GEJ, trapping acid in small pockets in and around theGEJ in patient with GERD. As gastric pressure increases while LESpressure decreases or remains constant, the functional LES pressuredecreases and the acid pockets are pushed up into the esophagus,resulting in esophageal acid exposure. Persons without GERD have no acidpockets. Acid pockets are defined by their length. Therefore, any pocketformation of acid having a length greater than 0 mm in the GEJ isconsidered an acid pocket in a GERD patient. In one embodiment, thesystems and methods of the present specification targeted at increasingthe relaxation response of the fundus reduce the occurrence of acidpockets by decreasing gastric pressure and increasing functional LESpressure thereby preventing the formation of acid pockets. In oneembodiment, the occurrence of acid pockets in the GEJ is reduced by atleast 10%. In one embodiment, the systems and methods targeted atincreasing the relaxation response of the fundus reduce the size of acidpockets in the GEJ. As functional LES pressure is increased by some ofthe systems and methods of the present specification, acid pockets haveless time to form in the GEJ. Therefore, the acid pockets that do formare smaller in size. In one embodiment, the systems and methods targetedat increasing the relaxation response of the fundus reduce the size ofacid pockets in the GEJ by at least 10%.

In one embodiment, the systems and methods of the present specificationtargeted at increasing the relaxation response of the fundus control thecontent of the post-prandial reflux. In one embodiment, the systems andmethods targeted at increasing the relaxation response of the fundusreduce the amount of acid in the reflux. In one embodiment, the amountof acid in the reflux is reduced by at least 10%.

In various embodiments, the efficacy of the above described therapy isdetermined by any one or combination of patient symptom reporting,esophageal pH monitoring, and esophageal impedance sensing. In variousembodiments, changes in gastric geometry are determined usingsingle-photon emission computed tomography (SPECT), magnetic resonanceimaging (MRI), ultrasound, barostat, and assessment of intragastricpressure.

The systems and methods of the present specification targeted atincreasing the relaxation response of the fundus are configured toachieve any one or combination of the following objectives: modulatemuscle tone of the fundus, change gastric geometry, increase gastricsize and/or volume, decrease gastric pressure, and increase functionalLES pressure (defined as the relationship between actual LES pressureand actual gastric pressure), all with the goal of reducing at least oneof a frequency of occurrence or an intensity of gastroesophageal refluxsymptoms in said patient.

In various embodiments, the systems of the present specification employstimulators, including macrostimulators or microstimulators, which canbe implanted with minimal invasiveness in the gastrointestinal system.Specifically, these devices can be beneficial for deep implant locationsfor which there is a natural orifice access providing closer proximitythan from outside the body. It should further be appreciated that thedevices are capable of stimulating all smooth muscle, not limited togastrointestinal (GI) smooth muscles and that the devices canadditionally be used to deliver stimulation to the proximal stomach orarea adjacent to the proximal stomach for treating various diseases thatcan be affected by gastric stimulation such as GERD, gastric motilityproblems and diabetes. The present application further incorporates byreference U.S. Pat. No. 6,901,295, PCT Patent Application NumberPCT/US08/56479, and U.S. patent application Ser. Nos. 12/030,222,11/539,645, 12/359,317, and 13/041,063 in their entirety.

The systems and methods disclosed herein can be used to achieve aplurality of different therapeutic objectives, including: treatment ofGERD; normalizing a patient's LES function; treatment of hypotensiveLES; increase resting or baseline LES pressure, aperistalsis of theesophagus; treating a patient to normalize esophageal pH, wherein saidnormalization is achieved when a patient has an esophageal pH value ofless than 4 for a period of time no greater than 5%, 10%, or 15% of a 24hour period or some fraction thereof; treating a patient to normalizeesophageal pH when in the supine position, wherein said normalization isachieved when a patient has an esophageal pH value of less than 4 for aperiod of time no greater than 3% of a 24 hour period; treating apatient to prevent damage to the patient's lower esophageal sphinctercaused by acid reflux; treatment of supine position induced diurnalGERD; treatment of activity-induced diurnal GERD; prevention of supineposition induced diurnal GERD; prevention of activity-induced diurnalGERD; treating a patient to mitigate damage to the patient's loweresophageal sphincter caused by acid reflux; treating a patient to stopprogression of damage to the patient's lower esophageal sphincter causedby acid reflux; treating a patient to minimize transient relaxations ofthe patient's lower esophageal sphincter; modifying or increasing LESpressure; modifying or increasing esophageal body pressure; modifying orimproving esophageal body function; modifying or improving esophagealsensation induced by the refluxate; modifying or improving the volume ofrefluxate; modifying or improving the clearance of the refluxate;reducing incidents of heartburn; modifying or improving esophageal acidexposure; increasing lower esophageal tone; detecting when a patientswallows; detecting when a patient is eating; treating agastrointestinal condition of a patient; treating a patient to minimizethe patient's consumption of certain solids or liquids; reducing patientsymptoms associated with diurnal gastrointestinal condition of apatient; treating a patient to minimize the patient's consumption ofcertain solids or liquids; reducing patient symptoms associated withGERD wherein such reduction is measured by an improvement in a patientquality of life survey and wherein said improvement is calculated byhaving a patient provide a first set of responses to said quality oflife survey prior to treatment and having a patient provide a second setof responses to said quality of life survey after said treatment andcomparing the first set of responses to said second set of responses;treating a patient for any of the above-listed therapeutic objectiveswith the additional requirement of avoiding tissue habituation, tissuefatigue, tissue injury or damage, or certain adverse reactions,including, but not limited to, chest pain, difficulty in swallowing,pain associated with swallowing, heartburn, injury to surroundingtissue, or arrhythmias. In various embodiments, the systems and methodsdisclosed herein can be used for treating a patient for any of theabove-listed therapeutic objectives wherein said treatment effectuates apartial or complete closure at the gastric cardia without impedingnormal swallow function in the patient. In other words, the gastriccardia is capable of opening for normal biological events while beingstimulated.

The disclosed treatment methods may be practiced within, and devices maybe implanted within, a plurality of anatomical regions to achieve one ormore of the therapeutic objectives described above, including increasingthe length of the LES high pressure zone and increasing the receptiverelaxation response of the fundus to cause a decrease in gastricpressure with an increase in functional LES pressure (gastroesophagealgradient). Treatment sites, or implantation sites, include: the loweresophageal sphincter; within 3 cm above and 3 cm below the LES;proximate to the LES; in the vicinity of the LES; the esophageal body;the upper esophageal sphincter (UES); within, proximate to, or in thevicinity of the gastro-esophageal junction; the esophagus, includingesophageal body, LES, and UES; proximate to the esophagus; in thevicinity of the esophagus; at or within the stomach, including thegastric cardia; nerves supplying the LES or gastro-esophageal junction;nerves supplying the esophageal body; nerves supplying the UES; ornerves supplying the esophagus, including the esophageal body, LES, andUES.

Additionally, it should be appreciated that a therapy which requires alower amount of energy increases the long-term functionality of astimulation device. Furthermore, accurate implantation of electrodes isimperative for improved efficacy and safety of these devices. Submucosaof organ systems, such as the area within the gastrointestinal tractbetween the muscularis mucosa and muscularis propria (two high impedancelayers), have a relatively lower electrode-tissue interface impedance(referred to as impedance herein) and are therefore desirable locationsfor lead implantation and improved efficacy of stimulation. In addition,the loose connective tissue of the submucosa provides an improvedenvironment for tunneling and creating pockets for lead implantation andmicrostimulator implantation. In one embodiment, the macrostimulator,microstimulator or their respective electrodes are implanted in thesubmucosa proximate to the LES, esophagus, or stomach to cause adjacentsmooth muscle contraction using electrical field stimulation. Additionalstimulator structures and/or electrodes may be placed in the adjacentmuscularis or serosa and used in combination with the aforementionedmacrostimulator or microstimulator. In another embodiment, thestimulator or electrodes are implanted in the gastrointestinal submucosato cause gastrointestinal muscle contraction using electrical fieldstimulation. Additional stimulator structures and/or electrodes may beplaced or proximate to in the adjacent gastrointestinal muscularismucosa, gastrointestinal serosa, or gastrointestinal nerves.

Treatment Methodologies

The present invention is directed toward multiple embodiments. Thefollowing disclosure is provided in order to enable a person havingordinary skill in the art to practice the invention. Language used inthis specification should not be interpreted as a general disavowal ofany one specific embodiment or used to limit the claims beyond themeaning of the terms used therein. The general principles defined hereinmay be applied to other embodiments and applications without departingfrom the spirit and scope of the invention. Also, the terminology andphraseology used is for the purpose of describing exemplary embodimentsand should not be considered limiting. Thus, the present invention is tobe accorded the widest scope encompassing numerous alternatives,modifications and equivalents consistent with the principles andfeatures disclosed. For purpose of clarity, details relating totechnical material that is known in the technical fields related to theinvention have not been described in detail so as not to unnecessarilyobscure the present invention.

In one embodiment, any stimulator device, including a macrostimulator ormicrostimulator, is programmed to implement one or more treatmentprotocols disclosed herein. It should be appreciated that the treatmentmethods described below are implemented in a stimulator, such as amacrostimulator or microstimulator, having a plurality of electrodes, orat least one electrode, including, but not limited to, unipolar orbipolar electrodes, an energy source, such as a battery or capacitor,and a memory, whether local to the stimulator or remote from thestimulator and adapted to transmit data to the stimulator, which storesa plurality of programmatic instructions wherein said instructions, whenexecuted by the macro/microstimulator, execute the stimulationtherapies, as described below.

The present specification discloses GERD treatment systems and methodsthat permit a patient, with one or more implanted stimulator systems asdescribed above, to engage in a swallow that causes liquid, food mass,food mass mixed with liquid, or any bolus of matter greater than lcc topass through the patient's esophagus (collectively referred to as a wetswallow or bolus swallow; wet swallow and bolus swallow shall be usedinterchangeably) while concurrently having one or more gastrointestinalanatomical structures, such as the upper esophagus, upper esophagealsphincter, esophagus, lower esophageal sphincter, the distal esophagus,the stomach, the gastric cardia, gastric fundus, and/or the vagus nerve,or any of the other anatomical structures described herein, be subjectedto electrical stimulation.

The prior art has conventionally taught that stimulation ofgastrointestinal structures, particularly the esophagus and loweresophageal sphincter, must cease when a patient engages in a swallow. Ithas now been unexpectantly determined that, if stimulated appropriately,such stimulation need not cease during, concurrent with, or in responseto a patient engaging in a wet swallow. The stimulation protocols,described below, are effectuated through the stimulation devicesdescribed herein and by the patent documents incorporated herein byreference. Such devices generally include any device for electricalstimulation of one or more structures in the esophagus and for use inthe treatment of GERD, comprising a pulse generator providing electricalstimulation, a power source for powering the pulse generator, one ormore stimulating electrodes operatively coupled or connected to thepulse generator wherein the electrode sets are adapted to be positionedwithin or adjacent to one or more anatomical structures describedherein. Preferably, the stimulating electrodes are designed to beimplanted predominantly in the submucosal layer or the muscularis layerof the esophagus. In one embodiment, a plurality of electrodes inelectrical communication with a macrostimulator is implantedpredominantly in the muscularis propria. In one embodiment, a pluralityof electrodes in electrical communication with a microstimulator isimplanted predominantly in the submucosal layer, if done endoscopically,and in the muscularis layer if done laparoscopically.

In various embodiments, the stimulation parameters, which areeffectuated through an electrical pulse that can be of any shape,including square, rectangular, sinusoidal or saw-tooth, may comprise anyof the variable ranges detailed in the table below.

TABLE 1 Pulse On Off Pulse Type Pulse Width Frequency Pulse AmplitudeCycle Cycle Short Pulse 1 -999 μsec 1-100 Hz Low (1-999 μAmp) 0-24 hrs0-24 hrs Intermediate (1-50 mAmp) and any values therein Intermediate1-250 msec 1-100 Hz Low (1-999 μAmp) 0-24 hrs 0-24 hrs PulseIntermediate (1-50 mAmp) and any values therein Intermediate 1-250 msec1-59 cpm Low (1-999 μAmp) 0-24 hrs 0-24 hrs Pulse Intermediate (1-50mAmp) and any values therein Long Pulse 251 msec-1 sec 1-59 cpm Low(1-999 μAmp) 0-24 hrs 0-24 hrs Intermediate (1-50 mAmp) and any valuestherein

In some embodiments, the stimulation parameters used to increase thelength of the high pressure zone of the LES and/or increase therelaxation response of the fundus include a pulse amplitude with a rangeof 3-20 mAmp, a pulse width with a range of 100 μsec-1 msec, a pulsefrequency with a range of 2 Hz-100 kHz, and a range of 3-24 sessions perday. In one embodiment, the stimulation parameters used to increase thelength of the high pressure zone of the LES and/or increase therelaxation response of the fundus include a pulse amplitude of 5-6 mAmp,a pulse width of 215 μsec, a pulse frequency of 20 Hz, and 6-12 sessionsper day. In other embodiments, the stimulation parameters used toincrease the length of the high pressure zone of the LES and/or increasethe relaxation response of the fundus include: a pulse width having arange of 30 μsec to 5 msec; a pulse amplitude having a range of 2 to 15mAmp; an on period ranging from 1 second to 23 hours, 59 minutes, and 59seconds; an off period ranging from 1 second to 23 hours, 59 minutes,and 59 seconds; a duty cycle ranging from 1 to 100%; and, a pulsefrequency. In some embodiments, the pulse frequency has a range of 1-100Hz or 1-59 cpm.

In various embodiments, the present specification discloses a method fortreating GERD by electrically stimulating a lower esophageal sphincteror nerve supplying the LES, an esophageal smooth muscle or a nervesupplying the esophageal smooth muscle, the gastric cardia or a nervesupplying the gastric cardia, and/or an area proximate the LES thatcauses an increase in the length of the high pressure zone of the LESand/or an increase in the relaxation response of the fundus withoutaffecting, preventing, prohibiting, or otherwise hindering a bolusswallow induced relaxation of the lower esophageal sphincter or bolusswallow induced esophageal body motility. In these embodiments, becauseelectrical stimulation need not be inhibited, there is no need to sensefor the bolus swallow in order to trigger a cessation of electricalstimulation and, therefore, a stimulator need not be programmed to sensefor the bolus swallow, to modify stimulation in response to a bolusswallow (even if the stimulation device has sensing capabilities), or tobe otherwise responsive to a bolus swallow. In one embodiment, thepresent specification discloses a method for treating GERD byelectrically stimulating a lower esophageal sphincter or nerve supplyingthe LES, an esophageal smooth muscle or a nerve supplying the esophagealsmooth muscle, the gastric cardia or a nerve supplying the gastriccardia, and/or an area proximate the LES that causes an increase in thelength of the high pressure zone of the LES without necessarilyincreasing the overall maximum pressure within the esophagus.

These stimulation processes normalizes lower esophageal sphincterfunction because they increase the length of the high pressure zone ofthe LES and/or increase the relaxation response of the fundus while notprohibiting or preventing a natural bolus swallow. These processes alsoa) do not affect gastric distension induced relaxation of the loweresophageal sphincter, b) improve the post bolus swallow augmentation ofthe LES pressure, and c) improve the esophageal body function, amongother therapeutic benefits, as described above.

Having eliminated the need to dynamically control the electricalstimulation based on swallow sensing, the system can be allowed toengage in automated “on/off” duty cycles that can range from 1 second to24 hours. During the “on” period, stimulation is preferably applied fora long enough period to enable recruitment of adequate nerves and/ormuscle fibers to achieve the desired pressure, function or effect. Thedesired “on” period is patient specific and is preferably calculatedbased on the time required to increase the LES high pressure zone to alength at least 10% greater than baseline plus additional time tomaintain the length enhancement (maintenance time) or to decreasegastric pressure by at least 10% plus additional time to maintain thereduced gastric pressure (maintenance time). In one embodiment, themaintenance time ranges from 1 second to 12 hours. While sensors are notrequired, in one embodiment, the “on” period can be determined, ortriggered by, sensors that sense changes in the LES, such as LESpressure changes, or changes in the esophagus. Those sensing electrodessense one or more of changes in gastrointestinal muscle tone orimpedance, peristaltic activity, esophageal peristalsis, esophageal pH,esophageal pressure, esophageal impedance, esophageal electricalactivity, gastric peristalsis, gastric electrical activity, gastricchemical activity, gastric hormonal activity, gastric temperature,gastric impedance, electrical activity, gastric pH, blood chemical andhormonal activity, vagal or other gastrointestinal neural activity andsalivary chemical activity and can be preferably positioned in oradjacent one or more of the esophagus, the stomach, the small intestine,the colon, the vagus or other gastrointestinal nerves and the vascularsystem.

The “off” period is preferably set in order to prevent development oftolerance or muscle fatigue, to improve device functionality, and tooptimize energy consumption from the battery. The desired “off” periodranges from 1 second to 24 hours. The desired “off” period is patientspecific and calculated based on the time required to change the LEShigh pressure zone length from its therapeutic value to the baselinevalue plus optional additional time to maintain the baseline length(relaxation time) or for the gastric pressure to return to itspre-treatment value plus optional additional time to maintain thebaseline pressure (relaxation time). In one embodiment, the relaxationtime ranges from 1 second to 12 hours. While sensors are not required,in one embodiment, the “off” period can be determined, or triggered by,sensors that sense changes in the LES, such as pressure, or changes inthe esophagus. Those sensing electrodes sense one or more of changes ingastrointestinal muscle tone or impedance, peristaltic activity,esophageal peristalsis, esophageal pH, esophageal pressure, esophagealimpedance, esophageal electrical activity, gastric peristalsis, gastricelectrical activity, gastric chemical activity, gastric hormonalactivity, gastric temperature, gastric impedance, gastric pH, bloodchemical and hormonal activity, vagal or other gastrointestinal neuralactivity and salivary chemical activity and can be preferably positionedin or adjacent one or more of the esophagus, the stomach, the smallintestine, the colon, the vagus or other gastrointestinal nerves and thevascular system.

Accordingly, in various embodiments, stimulation can be provided for afirst period to generate an increase in the length of the LES highpressure zone of a first threshold level, then the stimulation can belowered or removed while still maintaining the increase in the length ofthe LES high pressure zone at or above the first threshold level of highpressure zone length, thereby treating GERD and other gastrointestinalindications. Stimulation of greater than a first threshold level of LEShigh pressure zone length can be delivered within a time period of lessthan a first time period, thereby treating certain gastrointestinalindications. In one embodiment, the present specification discloses atreatment method in which stimulation, such as at or under 30 mAmp, 15mAmp, 10 mAmp, 8 mAmp, or any increment therein, is applied to achievean increase in LES high pressure zone length of less than a firstthreshold level and, concurrently, wet swallows are still enabledwithout terminating or decreasing the stimulation. In one embodiment,the present specification discloses a treatment method in whichstimulation, such as at or under 30 mAmp, 15 mAmp, 10 mAmp, 8 mAmp, orany increment therein, is applied and then terminated, after which thelength of the LES high pressure zone increases beyond a first thresholdlevel and, concurrently, wet swallows are still enabled. It should beappreciated that the stimulation parameters can be presented in terms oftotal energy applied. For example, the current stimulation parameterscan be replaced, throughout this specification, with preferred energylevels, such as at or under 6 millicoulombs (mC), 3 mC, 1 mC, 0.08 mC,or any increment therein.

In other embodiments, stimulation can be provided for a first period togenerate a decrease in gastric pressure of a first threshold level, thenthe stimulation can be lowered or removed while still maintaining thedecrease in gastric pressure at or below the first threshold level,thereby treating GERD and other gastrointestinal indications.Stimulation of greater than a first threshold level of gastric pressurecan be delivered within a time period of less than a first time period,thereby treating certain gastrointestinal indications. In oneembodiment, the present specification discloses a treatment method inwhich stimulation, such as at or under 30 mAmp, 15 mAmp, 10 mAmp, 8mAmp, or any increment therein, is applied to achieve a decrease ingastric pressure of less than a first threshold level and, concurrently,wet swallows are still enabled without terminating or decreasing thestimulation. In one embodiment, the present specification discloses atreatment method in which stimulation, such as at or under 30 mAmp, 15mAmp, 10 mAmp, 8 mAmp, or any increment therein, is applied and thenterminated, after which gastric pressure decreases beyond a firstthreshold level and, concurrently, wet swallows are still enabled. Itshould be appreciated that the stimulation parameters can be presentedin terms of total energy applied. For example, the current stimulationparameters can be replaced, throughout this specification, withpreferred energy levels, such as at or under 6 millicoulombs (mC), 3 mC,1 mC, 0.08 mC, or any increment therein.

It should further be appreciated that the treatment methodologiesdisclosed herein adjust for, take advantage of, account for, orotherwise optimally use a delayed, or latent, pressure response from theLES in response to electrical stimulation. Conventionally, the prior arthas taught that the LES instantaneously responds, either by contractingor relaxing, to the application of, or removal of, electricalstimulation. In the present treatment methodologies, the LES has adelayed or latent response to electrical stimulation, thereby resultingin a gradual increase in the length of the LES high pressure zone and/ora gradual decrease in gastric pressure after the application ofelectrical stimulation and a sustained increased length of the LES highpressure zone and/or decrease in gastric pressure after electricalstimulation is terminated, at least for certain stimulation parameters.Accordingly, a desired normalization of LES function can be achievedwell in advance of an expected GERD triggering event, such as eating,sleeping, napping, laying down, being in a supine position, bolusswallowing, or engaging in physical activity, by applying electricalstimulation before the GERD triggering event and then terminating thestimulation prior to, during, or after the GERD triggering event.Multiple embodiments of the present specification take advantage of thisdelayed response by stimulating the LES in a manner that does not causeimmediate contraction of the musculature or an immediate increase in LEShigh pressure zone length or immediate decrease in gastric pressure. Forexample, in one embodiment, stimulation is directed to the LES at alevel of no more than 6 mC repeated on a regular basis, for example 20times a second, for a specific period of time, for example 30 minutes.This results in lengthening of the LES high pressure zone and/or adecrease in gastric pressure that does not occur until after the initial5 minutes of stimulation and that continues once stimulation has beenterminated. In one embodiment, stimulation is directed to the LES at alevel of no more than 6 mC repeated on a regular basis, for example 20times a second, for a specific period of time, for example 30 minutes.This results in contraction of the LES and an increase in the length ofthe LES high pressure zone and/or a decrease in gastric pressure thatdoes not occur until after the initial stimulation has been initiatedand that continues or persists once stimulation has been terminated.

In these stimulation methodologies, a sub-threshold stimulation thatdoes not generate an instantaneous LES or esophageal function responseis applied for a predefined duration of time to achieve a therapeuticresponse. In one embodiment, sub-threshold stimulation means that anapplied stimulation does not substantially instantaneously achievecontraction of the LES. Sub-threshold stimulation may have stimulationparameters of less than 20 mAmp, less than 10 mAmp, or less than 8 mAmp.In one embodiment, a threshold or above threshold stimulation means thatan applied stimulation substantially instantaneously achievescontraction of the LES and may have stimulation parameters of greaterthan 20 mAmp, greater than 10 mAmp, or greater than 8 mAmp.Sub-threshold stimulation has multiple advantages, including improveddevice functionality, improved energy transfer in a wirelessmicrostimulator, improved patient safety, decreased patient adversesymptoms or side effects and decreased tolerance and/or fatigue.

Referring to FIG. 1 , a normal esophageal pressure profile 100 is shown.With deglutition, the peristaltic wave follows immediately after theupper esophageal sphincter (UES) relaxation, producing a lumen-occludingcontraction of the esophageal circular muscle. The contraction wavemigrates aborally at a speed that varies along the esophagus. Theperistaltic velocity averages about 3 cm/sec in the upper esophagus,then accelerates to about 5 cm/sec in the mid-esophagus, and slows againto approximately 2.5 cm/sec distally. The duration and amplitude ofindividual pressure waves also varies along the esophagus. The durationof the wave is shortest in the proximal esophagus (approximately 2seconds) and longest distally (approximately 5 to 7 seconds). Peakpressures average 53±9 mmHg in the upper esophagus, 35±6 mmHg in themid-portion, and 70±12 mmHg in the lower esophagus. These parameters canbe influenced by a number of variables including bolus size, viscosity,patient position (e.g., upright vs. supine), and bolus temperature. Forinstance, a large bolus elicits stronger peristaltic contractions thatmigrate distally at a slower rate than a small bolus. The peristalticvelocity is also slowed by outflow obstruction or increases inintra-abdominal pressure. Warm boluses tend to enhance, whereas coldboluses inhibit, the amplitude of peristaltic contractions.

Accordingly, bolus 102 propagates through the UES 112, esophageal body115, and LES 117 over a period of approximately, and typically, tenseconds. As the bolus 102 moves through the esophagus, portions of theUES 112, esophageal body 115, and LES 117 experience an increase inpressure. In a normal person, the baseline pressure range for the UES112 is between 34 and 104 mmHg, for the esophagus 115 is between 30 and180 mmHg, and for the LES 117 is between 10 and 45 mmHg. At the point ofLES relaxation 110, which occurs to permit the bolus to pass throughinto the stomach, the LES pressure decreases to below approximately 8.4mmHg. Notably, in a normal patient, post-swallow, the LES pressureincreases, after having decreased for the swallow, and then remains at ahigher baseline pressure level than just immediately prior to theswallow.

In various embodiments, the presently disclosed systems and methodsreturn an abnormally functioning LES to a state of normalcy,post-stimulation or post initiation of stimulation. The treatmentmethodology comprises implanting a stimulation device, as describedherein, and electrically stimulating the device to cause an increase inthe length of the LES high pressure zone and/or an increase infunctional LES pressure by decreasing actual gastric pressure throughmodulation of the tone of the fundus, in accordance with any of thestimulation methodologies described herein. After stimulation isterminated, one or more of the following functional parameters,characteristic of an abnormally functioning LES, achieves normalphysiological range: a) LES basal pressure (respiratory minima) returnsto a range of 15-32 mmHg, b) LES basal pressure (respiratory mean)returns to a range of 10-43 mmHg, c) LES residual pressure returns to arange of less than 15 mmHg, d) LES percent relaxation returns to a rangeof greater than 40%, e) LES duration of contraction returns to a rangeof 2.9 seconds to 5.1 seconds (3 cm above the LES), 3 seconds to 5seconds (8 cm above the LES), or 2.8 seconds to 4.2 seconds (13 cm abovethe LES), f) lower esophageal acid exposure during 24-hour pH-metryreturns to a range of pH<4 for less than 10%, and preferably less than5%, of total or less than 8% or preferably less than 3% of supine time,and/or g) esophageal reflux events return to less than 100 per 24 hourperiod or reduce by 50% as documented by impedance pH monitoring, i)normal bolus swallows return with complete bolus transit, defined asdetection of bolus exit in all 3 of the distal impedance channels and/orj) esophageal pH returns to a range equal to twice the normal, asdefined in the table below or any normative standards for the measuringdevice.

TABLE 2 Catheter-based dual-probe (distal and proximal) esophageal pHmonitoring Normal Variable Proximal (%) Distal (%) Time pH <4.0 (%)Total period <0.9 <4.2 Upright period <1.2 <6.3 Recumbent period <0.0<1.2 Distal = 5 cm above manometric defined proximal border of the LES.Proximal = 20 cm above manometric defined proximal border of the LES.Catheter free distal esophageal pH monitoring Normal Variable Distal (%)Time pH <4.0 (%) Total period <5.3 Upright period <6.9 Recumbent period<6.7 Distal = 6 cm above endoscopic defined gastroesophageal junction

Accordingly, the presently disclosed systems and methods modify one ormore of the aforementioned functional parameters characteristic of anabnormally functioning LES or the esophagus to that of a normally orimproved functioning LES or the esophagus, even after stimulation isterminated. By transforming an abnormally functioning LES or theesophagus to a normally or improved functioning LES or the esophagus,esophageal reflux, GERD, esophageal motility disorders or esophagealneural, muscular or neuromuscular disorders, can be effectively treated.

In another embodiment, the presently disclosed systems and methodsmodify an abnormally functioning LES or the esophagus to provide for anadequately functioning LES or esophagus post-stimulation. The treatmentmethodology comprises implanting a stimulation device, as describedherein, and electrically stimulating the tissue to cause an increase inthe length of the LES high pressure zone and/or an increase infunctional LES pressure by decreasing actual gastric pressure throughmodulation of the tone of the fundus, in accordance with any of thestimulation methodologies described herein. After stimulation isterminated, one or more of the following functional parameters,characteristic of an abnormally functioning LES, returns to aphysiological range sufficient to prevent esophageal reflux, GERD,esophageal motility disorders or esophageal neural, muscular orneuromuscular disorders: a) LES basal pressure, b) LES residualpressure, c) LES percent relaxation, d) LES duration of contraction, e)distal esophageal pH, f) esophageal reflux events, and g) esophagealbody function. Accordingly, the present invention modifies physiologicalparameters characteristic of an abnormally functioning LES, relative tothe patient's pre-treatment state, to that of an adequately functioningLES, even after stimulation is terminated. By transforming an abnormallyfunctioning LES to an adequately functioning LES, esophageal reflux,GERD, esophageal motility disorders or esophageal neural, muscular orneuromuscular disorders can be effectively mitigated.

In another embodiment, the present specification enhances the length ofthe high pressure zone of an abnormally functioning LES and/or decreasesgastric pressure post-stimulation. The treatment methodology comprisesimplanting a stimulation device, as described herein, and electricallystimulating the tissue to cause an increase length of the LES highpressure zone and/or an increase in functional LES pressure bydecreasing actual gastric pressure through modulation of the tone of thefundus, in accordance with any of the stimulation methodologiesdescribed herein. After stimulation is terminated, in some embodiments,LES high pressure zone baseline length is increased, relative to thepatient's pre-treatment state, by at least 5%, preferably 10%. Afterstimulation is terminated, in some embodiments, gastric pressure isdecreased, relative to the patient's pre-treatment state, by at least5%, preferably 10%. Accordingly, the presently disclosed methods andsystems enhance the length of the high pressure zone of an abnormalfunctioning LES and/or decrease gastric pressure, even after stimulationis terminated. By doing so, esophageal reflux, GERD, esophageal motilitydisorders or esophageal neural, muscular or neuromuscular disorders canbe effectively mitigated.

In another embodiment, the presently disclosed systems and methodsimprove, post-stimulation, at least one of a) esophageal body pressure,b) esophageal body contractility, c) esophageal body motility, d)esophageal body bolus transit, or e) esophageal body peristalsis,resulting in improved esophageal acid clearance after a reflux event,decreasing esophageal acid exposure time, and minimizing damage fromexposure of esophageal mucosa to gastro-duodenal refluxate. Thetreatment methodology comprises implanting a stimulation device, asdescribed herein, and electrically stimulating the tissue to cause anincrease in the length of the LES high pressure zone and/or an increasein functional LES pressure by decreasing actual gastric pressure throughmodulation of the tone of the fundus, in accordance with any of thestimulation methodologies described herein. After stimulation isterminated, at least one of a) esophageal body pressure, b) esophagealbody contractility, c) esophageal body motility, e) esophageal bodybolus transit, or f) esophageal body peristalsis improves and remains inan improved state while the stimulator is off.

In another embodiment, the presently disclosed systems and methodsachieve any of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein the patient's esophagushas a function, and treating the patient by applying electricalstimulation, wherein the stimulation causes an improvement in esophagealfunction. Esophageal function may include any one of esophagealpressure, bolus transit, esophageal perception, esophageal accommodationor esophageal clearance of the refluxate.

In another embodiment, the presently disclosed systems and methodsachieve any of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein the patient's esophagushas a function, and treating the patient by applying electricalstimulation, wherein the stimulation causes a non-instantaneous ordelayed improvement in esophageal function. Esophageal function mayinclude any one of esophageal pressure, bolus transit, esophagealperception, esophageal accommodation or esophageal clearance of therefluxate.

FIG. 2A is a graph depicting a wet swallow at baseline for a GERDpatient. In a typical GERD patient, the LES relaxes prior to a swallow205. Post-swallow, the LES pressure increases 210, which can be observedfor a short duration following the swallow, and then reverts to aresting tone 215. Gastric pressure 220 remains constant before, during,and after the swallow. In the absence of stimulation, gastric pressure220 is under only neural control, and is designed to remain constant asthe stomach expands and contracts with the ingestion and passage offood, respectively. It should be appreciated that the resting tone 215of the LES in the GERD patient is too low to prevent reflux. Theconstant gastric pressure level 220 overcomes the low resting pressure215 of the esophagus, causing reflux of gastric material into theesophagus.

FIG. 2B is a graph depicting one embodiment of an improved wet swallowwith stimulation targeted at increasing the receptive relaxationresponse of the fundus. Again, in the typical GERD patient, the LESrelaxes prior to a swallow 235. Post-swallow, the LES pressure increases240, which can be observed for a short duration following the swallow,and then reverts to a resting tone 245. The low resting tone 245 of theabnormally functioning LES is not enough to prevent reflux. However,with stimulation 250, the gastric pressure decreases from its constantlevel 260 to a reduced level 265. The reduced gastric level 265continues for a short time even after stimulation has ceased. Thedecrease in gastric pressure 265 is sufficient to result in an increasein functional LES pressure or the gastroesophageal pressure gradient,even with a low LES resting pressure 245. In other words, the decreasein gastric pressure 245 provided by the systems and methods of thepresent specification targeted at increasing the receptive relaxationresponse of the fundus is greater than the decrease in LES restingpressure 245 of the abnormally functioning LES. The relative higherpressure above the GEJ prevents gastric contents from refluxing into theesophagus.

FIG. 2C is a flow chart illustrating the steps involved in oneembodiment of a method of treating a patient with GERD by decreasinggastric pressure through electrical stimulation. At step 202, aphysician implants at least one stimulating electrode of an electricalstimulation system in accordance with the various embodiments of thepresent specification proximate the gastric fundus of a patient. Thesystem is then activated at step 204 to provide electrical stimulationto the fundus. Optionally, in one embodiment, a plurality of sensorspositioned in the stomach detects decrease in gastric pressure at step206. Optionally, at step 208, the system parameters are modified toprovide an appropriate amount of stimulation to maintain the decrease ingastric pressure for a desire period of time in accordance with varioustreatment protocols of the present specification.

FIG. 3A is an illustration of the distal portion of an esophagus 305 ofa patient with gastroesophageal reflux disease (GERD). The patient's LES310 does not function properly, allowing the reflux of gastric contentsfrom the stomach 325 up into the esophagus 305. Referring to FIG. 3 ,the patient suffering from GERD has a shortened length l of the highpressure zone 315 of the LES 310. A patient with GERD can have a highpressure zone 315 with a length l less than 1 cm. This results frominsufficient contraction of the circular muscle of the LES 310. Theshortened high pressure zone 315 is inadequate in preventinggastroesophageal reflux.

FIG. 3B is an illustration of the distal portion of an esophagus 335receiving stimulation targeted at increasing the length of the LES highpressure zone 345, in accordance with one embodiment of the presentspecification. Electrical stimulation results in the recruitment ofadditional muscle fibers in the LES 340. A greater portion of the LES340 contracts, resulting in an enhancement, or increase, in the lengthl_(s), of the high pressure zone 345. In one embodiment, the lengthl_(s), of a high pressure zone of an LES receiving stimulationrepresents an increase in length of at least 10% in relation to thelength l of FIG. 3A of a high pressure zone of an LES prior totreatment. The longer high pressure zone 345 functions as a longerbarrier to the reflux of gastric contents from the stomach 355 up intothe esophagus 335, thereby effectively treating GERD.

FIG. 3C is a flow chart illustrating the steps involved in oneembodiment of a method of treating a patient with GERD by increasing thelength of the LES high pressure zone through electrical stimulation. Atstep 302, a physician implants at least one stimulating electrode of anelectrical stimulation system in accordance with various embodiments ofthe present specification proximate the LES of a patient. The system isthen activated at step 304 to provide electrical stimulation to the LES.Optionally, in one embodiment, a plurality of sensors positioned in theesophagus detects an increase in the length of the LES high pressurezone at step 306. Optionally, at step 308, the system parameters aremodified to provide an appropriate amount of stimulation to maintain theincrease in length of the LES high pressure zone for a desire period oftime in accordance with various treatment protocols of the presentspecification.

Referring to FIGS. 4-7 , the presently disclosed methods and systemsenable different post-stimulation residual effects, including anincrease in LES pressure post-stimulation 410 followed by a decrease inLES pressure down to a stimulation state 405 over a period of 2 to 3hours (FIG. 4 ), a slow decrease in LES pressure post-stimulation 510back to a pre-stimulation LES pressure level 505 over a period of 1 to 2hours (FIG. 5 ), a continued increase in LES pressure post-stimulation610 followed by a decrease in LES pressure which still remains above apre-stimulation state 605 after a period of 2 to 3 hours (FIG. 6 ), andminimal to no increase in LES pressure during stimulation 705 and acontinued increase in LES pressure post-stimulation 710 followed by adecrease in LES pressure which still remains above a pre-stimulationstate after a period of 2 to 3 hours (FIG. 7 ).

In one embodiment, the present specification encompasses a method forcontrolling muscle action using electrical stimulation by a modulatedelectrical signal having carrier frequency in the range of 2 KHz-100 KHzand an on-off modulating signal having an “on” duration in the range of5 μs to 500 msec and, in particular, 200 μs.

In one embodiment, a pacemaker lead, such as a modified Medtronic 6416200 cm, is secured to the LES in a submucosal tunnel using endoclipsalong the body of the lead and exteriorized nasally. Stimulation isapplied using a 200 μsec to 3 msec pulse with a pulse amplitude of 1mAmp to 15 mAmp, more preferably 5 mAmp to 10 mAmp, pulse frequency ofpreferably less than 1 msec, more preferably 200 μs, and a pulse widthof 200 μsec. In various embodiments, the length of the patient's LEShigh pressure zone is increased by at least 5%, and more preferably byat least 10%. In various embodiments, gastric pressure is decreased byat least 5%, and more preferably by at least 10%. Additionally, invarious embodiments, transient LES relaxation is improved by at least5%, LES function is improved by at least 5%, esophageal body pressure isimproved by at least 5%, esophageal body function is improved by atleast 5%, symptoms of GERD are improved by at least 5%, esophageal acidexposure is improved by at least 5%, quality of life is improved by atleast 5%, caloric intake is improved by at least 5%, and/or weight isimproved by at least 5%.

These improvements are achieved without any affect on patient's swallowfunction, adverse symptoms, or cardiac rhythm disturbances. Theseimprovements are also achieved by avoiding continuous electricalstimulation, which yields problems of muscle fatigue, build up oftolerance, tissue damage, and excessively high requirements for localenergy storage, such as capacitor size or battery life.

In another embodiment, the stimulator may be operated using a pulsehaving a frequency of 20 Hz (1-100 Hz), a pulse amplitude of 1 μAmp-1Amp, more preferably 1-20 mAmp, and a pulse width of 1 μsec-1 msec, andmore preferably 100-500 μsec. The stimulator may also be stimulatedusing a pulse having a frequency of 20 Hz (1-100 Hz), a pulse amplitudeof 1-20 mA (1 μAmp-1 Amp), and a pulse width of 1-50 msec (500 μsec-100msec). The stimulator may also be stimulated using a pulse having afrequency of 5 cpm (1-100 cpm), a pulse amplitude of 1-20 mAmp (1 μAmp-1Amp), and a pulse width of 100-500 msec (1 msec-1 sec).

In certain applications, there is an advantage to combining neuralstimulation with direct muscle stimulation. Such applications include,for example, gastric stimulation for gastroparesis where a combinedeffect on gastric muscle and neural modulation can be synergistic inimproving both gastric emptying rates and symptoms associated withgastroparesis. Another example can be the treatment of chronic refluxdisease where both high frequency and low frequency pulses can havedesirable effects on maintaining adequate lower esophageal sphinctertone or function while modulating the perception of symptoms associatedwith GERD.

In certain applications where an implantable electrode or a leadlessdevice is used for delivering electrical stimulation, it is technicallymore feasible to apply lower pulse width (having higher frequencycomponents) than signals having wider pulse duration. The reason is thatirreversible electrochemical effects occur when the total chargetransfer through the electrode-tissue interface at any given timeincreases above a certain threshold. In these cases, electrolysis occurswhich releases metal ions into the tissue, damages the electrode, andcauses dangerous pH changes in the local tissue. This has negativeeffects on the electrode longevity and on the tissue and should beavoided especially in chronic applications where stimulation of the samesite using the same electrode or device is planned for an extendedperiod of time.

Some methods for overcoming the problems of using long pulse durationswere developed that attempt to enhance the capacitance of theelectrode-tissue interface so as to increase the threshold forirreversible effects, thereby increasing the maximal pulse width thatcan be used chronically. Electrode capacitance can be increased invarious ways, such as by enhancing effective electrode surface area bycoating (e.g. coating with iridium-oxide or titanium nitride), bychanging the electrode material, and/or by geometrical changes in theelectrode shape. These methods, however, have some undesirableconsequences, such as a significant increase in the manufacturing costof the electrode and/or making the electrode unsuitable for specificimplantation procedures. It is therefore useful to minimize the use oflong pulse durations.

Furthermore, it should be noted that the use of square wave pulses,which is very common in conventional electrical stimulation systems,contains energy in frequency bands that are higher than the base rate ofthe pulse width. In general, when a square wave is used then most of theenergy is delivered in the base rate and a portion of the energy isdelivered in frequencies that are multiples (harmonics) of such baserate. Consequently, when a wide pulse width is delivered at a lowfrequency rate, some energy is also delivered in higher bands (multiplesof the base rate) and also multiples of the reciprocal value of thepulse width. The practical effect, however, of these higher frequencycomponents (or harmonics) is relatively small since only a small portionof the energy is delivered in these bands. It should further beappreciated that some frequencies, especially very high ones, are notabsorbed in most tissues and can therefore be used as carriers to lowerfrequency signals that modulate them. Accordingly, high frequencies canbe used to transfer or carry energy to the tissue without anyphysiological effect. Recovery of the low frequency signal is performedusing a demodulator.

In light of the above, in one embodiment, a combination of low and highfrequency signals (e.g. a waveform including both a high frequencycomponent and a low frequency component) are delivered through anelectrode or a leadless stimulating device with the purpose of applyingtwo separate effects to the stimulated tissue and positively impactingLES high pressure zone length and functional LES pressure. The lowfrequency signal will be modulated on a high frequency carrier known tobe neutral to muscle tone whereas the low frequency signal will bedemodulated by the tissue itself and deliver a separate impact on thetissue, which is known to occur with a direct muscle stimulation usinglow frequency signals. The signal is designed to have a zero net chargedelivered to the tissue over durations shorter than 1 ms therebyallowing flexibility in electrode design far more than what would berequired if using a long pulse duration directly.

In one embodiment, referring to FIG. 8 , the modulation is achieved bypulse trains having a base high frequency and duration equal to thedesired long pulse width. Here, the stimulation train does not have anet zero charge; therefore, in order to discharge the electrode-tissuecapacitance, a 350 msec time period 805 can be deployed, using a lowimpedance pathway switched by the stimulation device. Alternatively, asingle negative discharging pulse can be applied once every 700 mseccycle 810. The low impedance connection can also preferably be appliedfollowing each of the 100 μsec pulses 815 thereby minimizing the maximalnet charge accumulated on the electrode-tissue capacitance. There areseveral advantages of this waveform configuration: 1) the longest pulseduration applied is 100 μsec thereby relaxing the demands on achronically implantable electrode capacitance that would have beenrequired for a 350 msec pulse duration; 2) a train duration of 350 msecadds a low frequency component which is known to have a direct positiveeffect on muscle tone; 3) there is a reduced energy requirement from thedevice, resulting from the lower total pulse durations; and 4) the totalstimulation result is optimized by a combination of two differentfrequency bands, each controlling the muscle through an independentphysiological mechanism.

In another embodiment, the present invention encompasses an apparatuscomprising a housing, pulse generator capable of generating square wavesin the frequency range of 2 KHz-100 KHz, conductive tissue interface,means for fixation of conductive tissue interface to muscle tissue,programmable control unit capable of delivering said pulse generatoroutput to the tissue intermittently whereas each “on” duration can beprogrammable in the range of 5 μsec to 500 msec and an “off” durationprogrammable in the same or different range. Optionally, the muscletissue is the LES, stomach, esophagus, or UES. Optionally, the carrierfrequency is in the range of 40 KHz-60 KHz and “on” duration is 300-400msec. Optionally, the signal structure may be triggered by other timingmechanisms, including various patient-specific attributes, activities,and states. Optionally, a control unit, which is separate from amicrostimulation device, includes a demodulator and a pulse generatorfor the high frequency carrier, transmits energy to the microstimulatorto power the pulse generator, and includes modulation information usinga different carrier frequency. Optionally, the stimulation devicecomprises multiple leads output and alternates a modulation signalbetween two or more stimulation locations where, while one location hasan “on” state, the other location has an “off” state, and vice-versa.

In another embodiment, the stimulator may be stimulated using an “on”phase and an “off” phase, wherein the on phase is between 1 minute and 1hour and the off phase is between 1 minute and 1 hour. Preferably, boththe on and off phases are between 5 and 30 minutes. In anotherembodiment, the stimulator or microstimulator may be stimulated using acombination of a low frequency pulse and an intermediate or highfrequency pulse. In one embodiment, the low frequency pulses aredelivered for a duration that is 1% to 1000% of the intermediate or highpulse duration.

In another embodiment, the stimulator may be stimulated using an “on”phase and an “off” phase, wherein the on phase is between 1 second and24 hours and the off phase is between 1 second and 24 hours. Preferably,the off phase is longer than the on phase. In this embodiment, thestimulator or microstimulator may be stimulated using a combination of alow frequency pulse and an intermediate or high frequency pulse. In oneembodiment, the low frequency pulses are delivered for a duration thatis 1% to 1000% of the intermediate or high pulse duration. In anotherembodiment a combination of same frequency pulse with varying amplitudecan be used. For example, a patient can receive intermittent orcontinuous stimulation at a lower amplitude with one or more sessions ofstimulation at a higher amplitude wherein the higher amplitude is atleast twice the lower amplitude.

It should be appreciated that, wherever stimulation parameters aredescribed, the stimulation may be initiated by “ramping up” to thestated stimulation levels or may be terminated by “ramping down” to anoff state. The ramp up and ramp down can be as slow or as fast asrequired to effectuate the required therapy.

In one embodiment, the programmed duty cycle, pulse frequency, pulsewidth, pulse amplitude of the stimulator and corresponding electrodeconfiguration are configured to trigger secretion of neurokinin A (NKA)or a similar peptide. The configuration of the frequency and amplitudeis set to efficiently achieve a clinically significant secretion withminimal energy. The session duration can make use of the longdegradation time of NKA and be configured to turn off stimulationfollowing the expected accumulation of sufficient NKA secretion.Electrode configuration, as further described below, can be adapted sothat the desired optimal session duration will alternate in differentregions using implantation of electrodes in different regions of theLES. The configuration of the stimulation to impact local NKA level canbe designed to achieve the required pressure curve as described in FIGS.4-7 .

It should further be noted that, because the stimulation device enablesthe therapeutically effective treatment of a plurality of ailments, asdescribed above, at currents below 15 mAmp, one can avoid subjecting thepatient to physical pain, sensation, or discomfort. The present systemcan achieve the therapeutic goals and effectively operate by deliveringlower stimulation levels for longer periods of time, such as bydelivering 3 mAmp for 10 minutes rather than 15 mAmp for 5 minutes. Thepulse frequency can be 20 Hz and the stimulation can be delivered lessthan five times per day, such as three times per day.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device, such as a macrostimulator ormicrostimulator, adapted to be implanted within or proximate thepatient's lower esophageal sphincter, esophagus, upper esophagealsphincter, stomach, gastric fundus, or gastric cardia and adapted toapply electrical stimulation to the patient's lower esophageal sphincteror gastric fundus; and programming, using, or operating said stimulationdevice, wherein said programming, use, or operation defines, uses, or isdependent upon a plurality of stimulation parameters that determine theapplication of electrical stimulation to the patient's lower esophagealsphincter or gastric fundus and wherein said stimulation parameters areselected, derived, obtained, calculated, or determined, at least inpart, to account for a latent, delayed, time-delayed, or future responseof the patient's lower esophageal sphincter or gastric fundus.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia and toapply electrical stimulation to the patient's lower esophageal sphincteror gastric fundus, wherein said lower esophageal sphincter or gastricfundus exhibits a latent, delayed, time-delayed, or future response toapplied electrical stimulation; and treating said patient by applyingelectrical stimulation based upon derived from, or dependent upon saidlatent, delayed, time-delayed or future response.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia and toapply electrical stimulation to the patient's lower esophageal sphincteror gastric fundus; and initiating, activating, beginning, or startingsaid electrical stimulation prior to a pre-defined or fixed time whereinsaid pre-defined or fixed time is associated with a GERD triggeringevent and wherein said initiation occurs prior to said pre-defined orfixed time by a minimum period, such as at least 5 minutes, 10 minutes,15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 12 hours, 24 hours, orany time increment therein.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia andadapted to apply electrical stimulation to the patient's loweresophageal sphincter or gastric fundus; and initiating, activating,beginning, or starting said electrical stimulation prior to apre-defined or fixed time wherein said pre-defined or fixed time isassociated with a GERD triggering event and wherein said initiationoccurs prior to said pre-defined or fixed time by a minimum period, suchas at least 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2hours, 3 hours, 12 hours, 24 hours, or any time increment therein; andterminating said electrical stimulation after said pre-defined or fixedtime has passed.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia andadapted to apply electrical stimulation to the patient's loweresophageal sphincter or gastric fundus; and programming, using, oroperating said stimulation device, wherein said programming, use, oroperation defines, uses, or is dependent upon a plurality of stimulationparameters that determine the application of electrical stimulation tothe patient's lower esophageal sphincter or gastric fundus and whereinsaid stimulation parameters are selected, derived, obtained, calculated,or determined, at least in part, to treat GERD without inhibiting,hindering, stopping, or preventing the patient from swallowing.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia andtreating said patient by applying electrical stimulation while thepatient swallows, during periods of esophageal motility, or duringesophageal peristalsis.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia andtreating said patient by applying electrical stimulation in accordancewith a preset period wherein said preset period is not dependent upon,influenced by, modified by, lengthened by, or shortened by aphysiological state of a patient.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia andtreating said patient by applying electrical stimulation in accordancewith a preset period wherein said preset period is not dependent upon,influenced by, modified by, lengthened by, or shortened by the patientswallowing, esophageal motility, esophageal peristalsis, or being in afeeding state.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia andtreating said patient by applying electrical stimulation that is notdependent upon, influenced by, modified by, lengthened by, or shortenedby a physiological state, biological parameter, sensed physiological orbiological parameters of a patient.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia andtreating said patient by applying electrical stimulation that is notdependent upon, influenced by, modified by, lengthened by, or shortenedby the patient swallowing, esophageal motility, esophageal peristalsis,or being in a feeding state.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia,wherein said lower esophageal sphincter has a high pressure zone havinga length and said stomach has a gastric pressure, and treating saidpatient by applying sufficient electrical stimulation to increase saidlength of said high pressure zone or decreasing said gastric pressurebut not to inhibit, hinder, stop, or prevent swallowing, esophagealmotility, esophageal peristalsis, or being in a feeding state.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia,wherein the lower esophageal sphincter has a function, and treating thepatient by applying sufficient electrical stimulation to improve saidfunction but not to inhibit, hinder, stop, or prevent swallowing,esophageal motility, or esophageal peristalsis or dissuade a patientfrom being in a feeding state.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia,wherein said lower esophageal sphincter has a pressure; and treatingsaid patient by applying electrical stimulation, wherein saidstimulation causes an increase in said pressure of at least 5% onlyafter an elapsed period of time of at least one minute.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia,wherein said lower esophageal sphincter has a high pressure zone havinga length; and treating said patient by applying electrical stimulation,wherein said stimulation causes an increase in said length of said highpressure zone of at least 5%, and more preferably by at least 10% onlyafter an elapsed period of time of at least one minute.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia,wherein said patient has a stomach having a gastric pressure; andtreating said patient by applying electrical stimulation, wherein saidstimulation causes a decrease in said gastric pressure of at least 5%,and more preferably by at least 10% only after an elapsed period of timeof at least one minute.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia,wherein said lower esophageal sphincter has a high pressure zone havinga length; and treating said patient by applying electrical stimulation,wherein said stimulation improves or normalizes lower esophagealfunction, or enhances or increases said length of said high pressurezone to a normal physiological range only after an elapsed period oftime or only after a delay of at least one minute.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's gastric fundus, esophagus, upper esophagealsphincter, stomach, gastric fundus, or gastric cardia, wherein stomachhas a gastric pressure; and treating said patient by applying electricalstimulation, wherein said stimulation improves or normalizes loweresophageal function or decreases said gastric pressure below a normalphysiological range only after an elapsed period of time or only after adelay of at least one minute.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia,wherein said lower esophageal sphincter has a high pressure zone havinga length and said stomach has a gastric pressure; and treating saidpatient by applying electrical stimulation, wherein said stimulationcauses a non-instantaneous or delayed increase in said length of saidhigh pressure zone or a decrease in said gastric pressure.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia,wherein the lower esophageal sphincter has a function, and treating thepatient by applying electrical stimulation, wherein the stimulationcauses a non-instantaneous or delayed improvement in the function.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, esophagus, upper esophagealsphincter, stomach, gastric fundus, or gastric cardia, wherein saidlower esophageal sphincter has a pressure; and treating said patient byapplying electrical stimulation, wherein said stimulation causes anon-instantaneous or delayed increase in said pressure and wherein saidnon-instantaneous or delayed increase in the pressure normalizes LESfunction, normalizes LES pressure, increases LES pressure to a normalphysiological range, or increases LES pressure by at least 3%.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia,wherein said lower esophageal sphincter has a high pressure zone havinga length; and treating said patient by applying electrical stimulation,wherein said stimulation causes a non-instantaneous or delayed increasein said length of said high pressure zone and wherein saidnon-instantaneous or delayed increase said length of said high pressurezone normalizes LES function, normalizes LES pressure, increases LESpressure to a normal physiological range, or increases LES pressure byat least 3%.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia,wherein said stomach has a gastric pressure; and treating said patientby applying electrical stimulation, wherein said stimulation causes anon-instantaneous or delayed decrease is said gastric pressure andwherein said non-instantaneous or delayed decrease in gastric pressurenormalizes LES function, normalizes functional LES pressure, increasesfunctional LES pressure to a normal physiological range, or increasesfunctional LES pressure by at least 3%.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia,wherein said lower esophageal sphincter has a high pressure zone havinga length and said stomach has a gastric pressure; and treating saidpatient by applying electrical stimulation, wherein said stimulationcauses a gradual increase in said length of said high pressure zone or agradual decrease in said gastric pressure.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia,wherein said lower esophageal sphincter has a high pressure zone havinga length and said stomach has a gastric pressure; and treating saidpatient by applying electrical stimulation, wherein said stimulationcauses an increase in said length of said high pressure zone or adecrease in said gastric pressure after said electrical stimulation isterminated.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia,wherein said lower esophageal sphincter has a high pressure zone havinga length and said stomach has a gastric pressure; and treating saidpatient by applying electrical stimulation having a first level, whereinsaid stimulation causes an increase in said length of said high pressurezone or a decrease in said gastric pressure after said electricalstimulation is decreased from said first level.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by enhancing the lengthof the high pressure zone, decreasing gastric pressure, or improving thefunction of the patient's lower esophageal sphincter.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives, wherein said patienthas a lower esophageal sphincter and a stomach and wherein said loweresophageal sphincter has a high pressure zone having a length and saidstomach has a gastric pressure, by increasing the length of the highpressure zone of the patient's lower esophageal sphincter or decreasingsaid gastric pressure through the application of electrical stimulationto the lower esophageal sphincter, esophagus, upper esophagealsphincter, stomach, gastric fundus, or gastric cardia, or areasproximate thereto.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives, wherein said patienthas a lower esophageal sphincter and a stomach and wherein said loweresophageal sphincter has a high pressure zone having a length and saidstomach has a gastric pressure, by increasing the length of said highpressure zone of the patient's lower esophageal sphincter or decreasingsaid pressure through the application of electrical stimulation to thelower esophageal sphincter, esophagus, upper esophageal sphincter,stomach, gastric fundus, or gastric cardia or areas proximate thereto,and wherein said increase in length of said high pressure zone or saiddecrease in pressure does not inhibit or otherwise hinder the patient'sability to swallow.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by modifying thepressure or function of the patient's lower esophageal sphincter.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by modifying thepressure or function of the patient's lower esophageal sphincter throughthe application of electrical stimulation to the lower esophagealsphincter or areas proximate thereto.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by enhancing the lengthof the high pressure zone, decreasing gastric pressure, or modifying thefunction of the patient's lower esophageal sphincter through theapplication of electrical stimulation to the lower esophageal sphincter,esophagus, upper esophageal sphincter, stomach, gastric fundus, orgastric cardia, or areas proximate thereto.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by enhancing the lengthof the high pressure zone, decreasing gastric pressure, or modifying thefunction of the patient's lower esophageal sphincter through theapplication of electrical stimulation to the lower esophageal sphincter,esophagus, upper esophageal sphincter, stomach, gastric fundus, orgastric cardia, or areas proximate thereto and wherein said increase inlength of said high pressure zone or said decrease in gastric pressuredoes not inhibit or otherwise hinder the patient's ability to swallow.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia, andtreating said patient by applying electrical stimulation in accordancewith at least one “on” period, wherein said “on” period is between 1second and 24 hours and is not triggered by, substantially concurrentto, or substantially simultaneous with an incidence of acid reflux, andat least one “off” period, wherein said “off” period is greater than 1second.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia, andtreating said patient by applying electrical stimulation, wherein apulse amplitude from a single electrode pair ranges from greater than orequal to 1 mAmp to less than or equal to 8 mAmp.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia, andtreating said patient by applying electrical stimulation having a pulseduration of approximately 200 μsec.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia, andtreating said patient by applying electrical stimulation having a pulseduration of approximately 1 msec.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia, andtreating said patient by applying electrical stimulation having a pulseenergy level of <10 mAmp, pulse duration of <1 second, and/or pulsefrequency of <50 Hz.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia, andtreating said patient by applying electrical stimulation having a pulseenergy level of 1 mAmp to 10 mAmp (preferably 1 mAmp), pulse duration ina range of 50 μsec to 1 msec (preferably 215 μsec), a pulse frequency of5 Hz to 50 Hz (preferably 20 Hz), pulse on time in a range of 10 minutesto 120 minutes (preferably 30 minutes), and/or pulse off time in a rangeof 10 minutes to 24 hours.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia, andtreating said patient by applying electrical stimulation to increase LESpressure above a baseline or threshold LES pressure, wherein said LESpressure remains above said baseline or threshold LES pressure aftertermination of electrical stimulation.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia, andtreating said patient by applying electrical stimulation to increase thelength of the LES high pressure zone above a baseline or threshold highpressure zone length, wherein said length of said LES high pressure zoneremains above said baseline or threshold high pressure zone length aftertermination of electrical stimulation.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia, andtreating said patient by applying electrical stimulation to decreasegastric pressure below a baseline or threshold pressure level, whereinsaid gastric pressure remains below said baseline or threshold pressurelevel after termination of electrical stimulation.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's lower esophageal sphincter, esophagus, upperesophageal sphincter, stomach, gastric fundus, or gastric cardia, andtreating said patient by applying electrical stimulation to increase LEStone above a threshold LES tone, wherein said LES tone remains abovesaid threshold LES tone after termination of electrical stimulation.

In one embodiment, the presently disclosed systems and methods achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within orproximate the patient's gastric fundus, esophagus, upper esophagealsphincter, stomach, gastric fundus, or gastric cardia, and treating saidpatient by applying electrical stimulation to decrease fundus tone belowa threshold fundus tone, wherein said fundus tone remains below saidthreshold fundus tone after termination of electrical stimulation.

In one embodiment, the presently disclosed systems and methods provide amacrostimulator programmed, adapted to, or configured to perform any ofthe aforementioned methods or treatment protocols.

In one embodiment, the presently disclosed system and methods provide amacrostimulator comprising at least one electrode, an energy source, anda pulse generator in electrical communication with the at least oneelectrode and energy source, wherein said pulse generator is programmed,adapted to, or configured to perform any of the aforementioned methodsor treatment protocols.

In one embodiment, the presently disclosed systems and methods provide amicrostimulator programmed, adapted to, or configured to perform any ofthe aforementioned methods or treatment protocols.

In one embodiment, the presently disclosed systems and methods provide amicrostimulator comprising at least one electrode, an energy source, anda pulse generator in electrical communication with the at least oneelectrode and energy source, wherein said pulse generator is programmed,adapted to, or configured to perform any of the aforementioned methodsor treatment protocols.

Such treatment methods may be combined, directed toward any of theaforementioned therapeutic objectives, and/or implemented throughstimulating any of the aforementioned anatomical areas. The treatmentmethods may be further modified by using specific stimulationparameters, open loop data processes, closed loop data processes, thepatient's physical position and degree of activity, the patient's eatingstate, timing, quantity or content thereof, certain physiologicalparameters sensed by the device, including LES pressure, gastricpressure, or anti-habituation methods to prevent anatomical habituationto a specific set of stimulation parameters. Additionally, because thedevice can operate on a time-based schedule and not necessarily onphysiological triggers (although a physiological trigger can be anoptional embodiment), stimulation schedules can be tailored to userbehavior and/or routine. For example, stimulation therapy can bedelivered or stimulation energy can be transmitted at times that aremost convenient and least disruptive to the patient's activities ofdaily living, such as only scheduling stimulation while the patient issleeping, relaxing, or watching TV and scheduling stimulation only aftermealtimes. Such additional embodiments are described below.

Open Loop Programming

In one optional embodiment, the stimulation parameters, including pulsewidth, pulse frequency, pulse amplitude, ramp rates, and/or duty cycle,can be modified by a physician using data sensed by, stored within, ortransmitted from the stimulation device, data sensed by, stored within,or transmitted from a sensor implanted in the patient, and/or datacaptured by an external computing device used by a patient. A stimulatordevice having a local memory, or a transmitter capable of communicatingsensed information to a remotely located memory or memory external tothe patient, captures a plurality of sensed data, as discussed ingreater detail below. Concurrently, a patient controlled computingdevice, such as a laptop, personal computer, mobile device, or tabletcomputer, which is external to the patient is used by the patient tostore data input by the patient relevant to evaluating, monitoring, andadjusting the operation of the stimulator. Both the stimulator captureddata and patient inputted data is then transmitted to a physiciancontrolled device, as described below, to enable the physician toproperly evaluate, monitor, and modify the stimulation parameters.

In one embodiment, the patient-controlled computing device comprises aplurality of programmatic instructions that, when executed, generate adisplay which prompts a user for, and is capable of receiving input fromthe user, information regarding the user's food intake, the timing ofsuch food intake, exercise regimen, degree and extent of physicalsymptoms, incidents of acid reflux, when the user sleeps, when the userlays down, type of food being consumed, quantity of food, among othervariables. This data can be captured and stored locally and/ortransmitted to a remote server for access by a physician. If accessedremotely by a physician, the physician can transmit alerts back to thepatient, via a network in communication with the computing device orconventional communication systems, such as email, text messaging orphone, to confirm dose amounts, patient state information, or providefor therapy adjustment.

In one embodiment, the stimulator captured data includes whatstimulation parameters were used and when, the sensed LES pressureprofile within the high pressure zone, including the percentage oramount of time the LES high pressure zone was lengthened beyond acertain threshold level, such as greater than 10%, or beyond a 2′threshold level, such as greater than 20%, the occurrence of t-LESRs,esophageal pH, supine events, degree of physical movement, among othervariables.

In another embodiment, the stimulator captured data includes whatstimulation parameters were used and when, the sensed gastric pressureprofile, including the percentage or amount of time the gastric pressurewas decreased beyond a certain threshold level, such as greater than10%, or beyond a 2^(nd) threshold level, such as greater than 20%, theoccurrence of t-LESRs, esophageal pH, supine events, degree of physicalmovement, among other variables.

The patient-inputted data, when combined with the stimulator captureddata, can provide a holistic view of the patient's condition and theefficacy of a stimulation regimen. In particular, as patient symptomsare mapped to stimulation parameters and analyzed in relation to food ordrink intake, sleep, and exercise regimens, a physician will be able todetermine how best to modify the stimulation parameters, including dutycycle, stimulation initiation times or triggers, stimulation terminationtimes or triggers, pulse width, pulse amplitude, duty cycle, ramp rates,or pulse frequency, to improve patient treatment. As further discussedbelow, the physician will receive both the patient-captured andstimulation device captured data into a diagnostic terminal that can beused to process the information and transmit new stimulation parameters,if necessary, to the stimulation device. For example, the physician canmodify the stimulation parameters in a manner that would lower theincidents of reported acid reflux, generalized pain, pain whileswallowing, generalized discomfort, discomfort while swallowing, or lackof comfort during sleeping or physical exercise. The physician can alsomodify the stimulation parameters, including the initiation andtermination of stimulation, to better match one or more GERD triggeringevents, such as eating, sleeping, lying down, or engaging in physicalactivity. The physician can also modify the stimulation parameters,including the initiation and termination of stimulation, to better matchthe patient's personal work or vacation schedule.

Additionally, alerts can be created that can be either programmed intothe patient-controlled device or stimulation device which serve tonotify the patient of a device malfunction, a recommendation to take adrug, a recommendation to come back for a checkup, among othervariables. Those alerts can also be transmitted, via a computingnetwork, to the physician. Furthermore, external data sources, such asdemographic data or expert protocols, can be integrated into thephysician system to help the physician improve the diagnostic andevaluation process and optimize the programmed set of stimulationparameters.

It should further be appreciated that, as the patient controlled deviceand stimulator device accumulate data that maps the therapeutic regimenagainst the patient's activities and symptoms, the patient controlleddevice will be able to determine, and therefore inform the patient of,patterns which tend to increase or decrease the incidents of GERD,including types of food, quantity of food, timing of eating, among othervariables.

Closed Loop Programming

In one optional embodiment, the stimulation parameters, including pulsewidth, pulse frequency, pulse amplitude, initiation of stimulation,triggers for stimulation, termination of stimulation, triggers toterminate stimulation, ramp rates, and/or duty cycle, can be dynamicallyand intelligently modified by the stimulation device using data sensedby, stored within, or transmitted from the stimulation device, datasensed by, stored within, or transmitted from a sensor implanted in thepatient, and/or data captured by, stored within, and/or transmitted froman external computing device used by a patient.

As discussed above, data maybe captured by a patient-controlled deviceand/or the stimulator device. In this embodiment, a stimulator isfurther programmed to intelligently modify stimulation parameters,without physician input, based upon sensed data and/or patient inputs.In various embodiments, a stimulator determines that the length of theLES high pressure zone fails to increase, gastric pressure fails todecrease, or LES function fails to improve above a predefined threshold,even after a predefined amount of stimulation, and, accordingly,automatically modifies the stimulation parameters, within a preset rangeof operation, to yield an improvement in LES high pressure zone increaseor gastric pressure decrease. In one embodiment, a stimulator determinesthat the length of the LES high pressure zone, gastric pressuredecrease, or LES function improves significantly above a predefinedthreshold, after a predefined amount of stimulation, or maintains alevel above a predefined threshold and, accordingly, automaticallymodifies the stimulation parameters, within a preset range of operation,to yield an improvement in LES high pressure zone length, gastricpressure decrease, or LES function.

In one embodiment, a stimulator determines the length of the LES highpressure zone or decrease in gastric pressure remains above a predefinedthreshold level for a sufficient amount of time such that a subsequentpre-programmed stimulation session or sessions can be postponed orcancelled. In one embodiment, a stimulator device monitors the length ofthe LES high pressure zone or gastric pressure and initiates stimulationonly when said length falls below a predetermined threshold or saidgastric pressure increases above a predetermined threshold.Preprogrammed stimulation may be modified in order to continue orincrease in energy, duration, or frequency until the length of the LEShigh pressure zone rises above a predetermined threshold or gastricpressure decreases below a predetermined threshold. The length of theLES high pressure zone and/or gastric pressure threshold may bedynamically modified based upon sensed data.

In one embodiment, a stimulator determines that esophageal pH isindicative of incidents of acid reflux above a predefined thresholdlevel, and, accordingly, automatically modifies the stimulationparameters, within a preset range of operation, to yield an improvementin the length of the LES high pressure zone increase or gastric pressurereduction to lower such incidents. In one embodiment, a stimulatorreceives a communication from an external patient controlled deviceindicating that the patient is reporting a number of adverse incidentsabove a predefined threshold, such as acid reflux, generalized pain,pain while swallowing, generalized discomfort, discomfort whileswallowing, lack of comfort when sleeping, etc. and, accordingly,automatically modifies the stimulation parameters, within a preset rangeof operation, to yield a lower level of such incidents. In oneembodiment, a stimulator receives a communication from an externalpatient controlled device detailing a schedule of potentially GERDtriggering events, including sleep times, eating times, or exercisetimes, and, accordingly, automatically modifies the stimulationparameters, within a preset range of operation, to properly account forsuch GERD triggering events.

In one embodiment, the stimulator operates using both open loop andclosed loop programming. Stimulation parameters may be established usingopen loop programming methods, as described above, and then modifiedthrough the aforementioned closed loop programming methods. Stimulationparameters may also be established using closed loop programmingmethods, as described above, and then modified through theaforementioned open loop programming methods.

Stimulation Modification Based On Sensed Data

It should be appreciated that the stimulation system may stimulate basedon a plurality of data, including based on the length of the LES highpressure zone registering below a predefined threshold, based on gastricpressure registering above a predefined threshold, based on a patient'spH level, based on the patient's physical orientation, based on thepatient's meal intake, or based on a predefined time period, among othertriggers. It should also be appreciated that the controller may initiateor stop a stimulation based on a plurality of triggers, including basedon the length of the LES high pressure zone exceeding a predefinedthreshold, based on gastric pressure decreasing below a predefinedthreshold, based on a patient's pH level, based on the patient'sphysical orientation, or based on a predefined time period, among othertriggers.

Using various data sensors, including, but not limited to impedance,electrical activity, piezoelectric, pH, accelerometer, inclinometer,ultrasound-based sensors, RF-based sensors, or strain gauge, the systemcan determine whether a patient is eating, how much the patient iseating, how long the patient is eating, and/or what the patient iseating, and, based on that information, adjust stimulation parametersaccordingly. In particular, pH data may be used to determine what kindof food a patient is eating, where the type of food is defined in termsof its acidity.

In one embodiment, the stimulator system senses the length of the LEShigh pressure zone and initiates stimulation of the LES when said lengthis below a pre-defined threshold level for a predefined period of timeand terminates stimulation of the LES when said length is above apre-defined threshold level for a predefined period of time. The lengthof the LES high pressure zone may be determined by sensing andprocessing impedance measurements, electrical activity measurements,strain gauge, and/or piezoelectric measurements. One or more of thevarious measurements are constantly measured to create a contiguous highpressure zone length profile. Based upon the length profile, thestimulator can modify stimulation parameters, including pulse amplitude,pulse width, duty cycle, pulse frequency, stimulation initiation time,ramp rate, or stimulation termination time, to achieve, with respect tosaid length, an absolute amount of change, a percentage amount ofchange, increases or decreases above or below a threshold value,increases or decreases based on time, increases or decreases based on alength slope, among other measures of change.

In another embodiment, the stimulator system senses gastric pressure andinitiates stimulation of the gastric fundus when said gastric pressureis above a pre-defined threshold level for a predefined period of timeand terminates stimulation of the fundus when said gastric pressure isbelow a pre-defined threshold level for a predefined period of time.Gastric pressure may be determined by sensing and processing impedancemeasurements, electrical activity measurements, strain gauge, and/orpiezoelectric measurements. One or more of the various measurements areconstantly measured to create a contiguous gastric pressure profile.Based upon the pressure profile, the stimulator can modify stimulationparameters, including pulse amplitude, pulse width, duty cycle, pulsefrequency, stimulation initiation time, ramp rate, or stimulationtermination time, to achieve, with respect to said pressure, an absoluteamount of change, a percentage amount of change, increases or decreasesabove or below a threshold value, increases or decreases based on time,increases or decreases based on a length slope, among other measures ofchange.

In another embodiment, the stimulator system uses various data sensorsto determine the pulmonary, intra-thoracic, or intra-abdominal pressureand, based on pulmonary, intra-thoracic, or intra-abdominal pressure,create a patient-specific dose, such as a specific pulse amplitude,pulse width, duty cycle, pulse frequency, stimulation initiation time,ramp rate, or stimulation termination time, required to affect LES tone,pressure, or function to the levels needed by that patient.

In another embodiment, the stimulator system uses various data sensorsto determine the esophageal temperature and, based on that temperaturereading, create a patient-specific dose, such as a specific pulseamplitude, pulse width, duty cycle, pulse frequency, stimulationinitiation time, ramp rate, or stimulation termination time.

In another embodiment, the stimulator system uses various data sensorsto determine the esophageal pH and, based on that pH reading, create apatient-specific dose, such as a specific pulse amplitude, pulse width,duty cycle, pulse frequency, stimulation initiation time, ramp rate, orstimulation termination time.

In another embodiment, the stimulator system uses a combination of datainputs from the above described sensors to generate a total score fromwhich a stimulation therapeutic regimen is derived. For example, if thepatient has not eaten for a long time and lays down, a lower (or no)therapy dose would be delivered. Since GERD is an episodic disease andcertain periods are more vulnerable to a reflux event than others,detecting various patient parameters by various means and using them inan algorithm enables clinicians to target those specific reflux events.In addition, in various embodiments, multiple algorithms are programmedinto the stimulator device so that treatment can be tailored to varioustypes of GERD, based upon input relayed by the sensors. In oneembodiment, data from any combination of one or more of the followingparameters is used by an algorithm to determine stimulation protocol:patient feed state including type of intake (via patient input or eatingdetection by a physical sensor that can detect and/or evaluateliquids/solids/caloric value); patient position (viainclinometer/accelerometer); patient activity (viaaccelerometer/actimeter); patient reflux profile (via patient input/pHrecording); the length of the LES high pressure zone; LES pressure; LESelectrical activity; LES mechanical activity (via accelerometer in theLES, pressure sensor, impedance measure or change thereof); gastricpressure; gastric electrical activity; gastric chemical activity;gastric temperature; gastric mechanical activity (via an accelerometerin the stomach, pressure sensor, impedance measurement and changes);patient intuition; vagal neural activity; and, splanchnic neuralactivity. Based on input from one or more of the above parameters, thealgorithm quantifies the vulnerability for a reflux event and modifiesaccordingly the amplitude, frequency, pulse-width, duty cycle, ramprate, and timing of stimulation treatment. The table below lists theparameters, measurements, and values used in an exemplary treatmentprotocol of one embodiment of the present invention.

TABLE 3 Parameter Measurement Value Length of LES High Normal 0 PressureZone Low 1 Gastric Pressure Low 0 Normal 1 LES Pressure Normal 0 Low 1Inclination Upright 0 Supine 1 Feed State Fasting/Pre- 0 prandialPost-prandial 1 Time of the day Day time 1 Night time 0 Fat content ofmeal Low 0 High 1 Patient pH Profile Low-risk period 0 High-risk period1 Patient Symptom Low-risk period 0 Input High-risk period 1 GastricActivity Food Absent 0 Food Present 1 Upright Activity Low 0 Level High1 Supine Activity Level High 1 Low 0 Patient Intuition Low Likelihood 0High Likelihood 1

In the table above, each individual parameter is given a score of 1 or 0depending on the value measured. In one embodiment, a summary score istabulated using one or more parameters in the above exemplary algorithmscoring system to determine patient vulnerability to a reflux event.Based on the score, the treatment parameter is modified. Patients with ahigher summary score are indicated for a greater level of treatment. Forexample, a patient with normal LES pressure in the upright position anda pre-prandial state will be at minimal risk for a reflux event and notherapy will be indicated. Conversely, a patient with low LES pressurein the upright position and an immediate post-prandial state will be atthe highest risk for a reflux event and would receive the highest levelof GERD therapy. A patient with a low, or short, length of the LES highpressure zone would be at high risk for a reflux event and would receivea high level of GERD therapy.

In one embodiment, a measured parameter is used as a modifier foranother parameter. For example, gastric activity showing food absentdoes not have an individual score but modifies the feed state score froma post-prandial score to a fasting/pre-prandial score. In anotherembodiment, a measured parameter has an absolute value that is notimpacted by other measured parameters. For example, patient intuition ofa high likelihood of a reflux event is an absolute parameter thatdelivers the highest level of GERD therapy irrespective of other sensedparameters.

In one embodiment, the scoring system for certain individual parametersis a scale rather than a binary score. For example, in one embodiment,the score given to LES pressure is within a range from 0-5 based onduration of low pressure. With each incremental 5 minute duration of lowLES pressure, the score increases by one increment. In anotherembodiment, the score given to gastric pressure is within a range from0-5 based on duration of low pressure. With each incremental 5 minuteduration of normal or high gastric pressure, the score increases by oneincrement.

In another embodiment, different weight is given to differentparameters. For example, in one embodiment, low LES pressure is given anabsolute score higher than post-prandial feed state.

In another embodiment, the scoring system is tailored to be patientspecific. In one embodiment, for example, for a patient with low symptompredictability as ascertained by symptom association with a standard pHtest, patient symptom input is given a lower weight. In anotherembodiment, for a patient with mostly upright reflux on pH testing, theupright position is given a greater weight than the supine position. Inyet another embodiment, for a patient with exercise induced reflux, agreater weight is given to upright activity while the same parameterreceives a low weight or is eliminated from the algorithm in a patientwithout exercise induced reflux.

Accelerometer/Inclinometer Based Stimulation System

In one embodiment, the implantable device includes an accelerometer orinclinometer and a pre-programmed supine stimulation mode intended toautomatically provide the patient with additional stimulation sessionsduring extended time periods in which the patient is in the supineposition, as noted by said accelerometer/inclinometer. When the mode isenabled by a programmer, a supine position detection triggers additionalstimulation sessions based on pre-set programmable conditions. In oneembodiment, additional stimulation sessions will be initiatedautomatically when the following two conditions are met: 1) the patientis supine (based on a programmable range of inclination) for a minimumamount of time (based on pre-set time ranges) and 2) no stimulation wasapplied recently (maximal time programmable). In another embodimentspecific for GERD patients, the implantable device inhibits or does notschedule stimulation where the accelerometer or inclinometer detects asupine phase or position.

In one embodiment, the supine stimulation mode can be enabled ordisabled by the user via a programmer interface. The supine stimulationmode is available when the implantable device is in “cyclic” and “dose”modes, but not available (grayed out) when the device is in “continuous”and “off” modes. In another embodiment, the supine stimulation mode canbe implemented in conjunction with other stimulation modes, as describedabove, be the only mode of stimulation, or be disabled. In addition,when active, the supine stimulation mode may or may not overrideregularly scheduled stimulations or manually applied stimulations,depending on the programming. Further, when active, the supinestimulation mode may or may not deliver the same stimulation therapyprofile as programmed in the “cyclic”, “dose”, or other modes, asapplicable, depending on the programming.

In one embodiment, when the supine stimulation mode is enabled, anadditional set of specific programmable parameters becomes active on theprogrammer interface. This set includes the following parameters: supinetime; supine time percentage; supine refractory time; supine level;supine retrigger time and, supine cancel.

Supine time defines the period of time that is required for the patientto be in a supine position in order for the first condition listed aboveto be met. Supine time is programmable to a certain time period by theuser. In one embodiment, supine time is set to 1 minute. In anotherembodiment, supine time is set to 5 minutes. In another embodiment,supine time is set to 30 minutes. In yet another embodiment, supine timeis set to 60 minutes, or smaller increments thereof.

Supine time percentage defines the minimum percentage of data pointsrequired during the supine time in order for the first condition listedabove to be met. Supine time percentage is programmable to a certainpercentage by the user. In one embodiment, supine time percentage is setto 50 percent. In another embodiment, supine time percentage is set to70 percent. In another embodiment, supine time percentage is set to 90percent, or smaller increments thereof.

Supine refractory time defines the minimal amount of time required tohave passed from the end of the last stimulation session (scheduled,manual, or supine stimulation) before a new stimulation session may beinitiated via the supine stimulation mode. Supine refractory time isprogrammable to a certain time period by the user. In one embodiment,supine refractory time is set to 30 minutes. In another embodiment,supine refractory time is set to 60 minutes. In another embodiment,supine refractory time is set to 120 minutes. In yet another embodiment,supine refractory time is set to 180 minutes. FIG. 9 is an illustrationof a timeline 900 depicting a stimulation session 905 followed by asupine refractory time period 910. The supine refractory time period 910begins immediately after the end of the stimulation session 905 andcontinues through its pre-programmed duration. No additional stimulationinitiated by the supine stimulation mode can begin until the supinerefractory time period 910 has ended.

Supine level defines the level of inclination required to achieve asupine posture. Supine level is programmable to a range of degrees bythe user. In one embodiment, where the supine level is measured relativeto a horizontal body, supine level is set between 170 and 200 degrees.In another embodiment, supine level is set between 160 and 200 degrees.In another embodiment, supine level is set between 150 and 200 degrees.In yet another embodiment, supine level is set between 140 and 200degrees. In another embodiment, where the supine level is measuredrelative to a vertical baseline, supine level is set to an angle of 50,60, 70, or 80 degrees, where 0 degrees is a vertical position and 90degrees is a horizontal position.

Supine cancel defines the maximum amount of time that can elapse betweenthe end of a stimulation therapy session triggered by supine stimulationmode and the start of a regularly scheduled stimulation therapy sessionthat will cancel the regularly scheduled stimulation therapy session.Supine cancel is programmable to a certain time period by the user. Inone embodiment, supine cancel is set to 30 minutes. In anotherembodiment, supine cancel is set to 60 minutes. In another embodiment,supine cancel is set to 120 minutes. In yet another embodiment, supinecancel is set to 240 minutes. FIG. 10 is an illustration of a timeline1000 depicting a stimulation session 1005 triggered by supinestimulation mode followed by a supine cancel period 1010. The supinecancel period 1010 begins immediately after the end of the supinestimulation mode stimulation session 1005 and continues through itspre-programmed duration. Any regularly scheduled stimulation sessionscheduled during the supine cancel period 1010 will not be initiated.

Supine retrigger defines the maximum amount of time that may elapsebetween the end of a stimulation therapy session triggered by supinestimulation mode and the initiation of another stimulation. In oneembodiment, the supine retrigger period is programmable and may have avalue of 2 4, 6, or 8 hours, or any increment therein. In anotherembodiment, after a predefined threshold, such as 75%, of a supineretrigger period has passed, the stimulator initiates a post-sleepingstimulation, in anticipation of a breakfast meal event, if a verticalposition is sensed. In another embodiment, the stimulator does notinitiate a post-sleeping stimulation if a vertical position is sensed ifless than a predefined threshold, such as 75%, of a supine retriggerperiod has passed. It should be appreciated that an automatically setpost-sleeping stimulation is optional and that stimulation may simply bepreset for a particular time of the day.

Modifications to Prevent Habituation or Fatigue

Stimulation parameters may also be periodically modified, in accordancewith a predefined schedule or dynamically by real-time physician orpatient control, to reduce, avoid, or prevent the occurrence of musclefatigue, habituation, and/or tolerance. Manipulation of the length ofthe “on” and “off” cycles can be performed while still obtaining thedesired level of LES function. In one embodiment, the length ofstimulation time to achieve the therapeutic goal can be decreased whilethe stimulation off time required for LES function to return to baselinecan be increased. Less time spent in the “on” cycle will result in fewerincidents of muscle fatigue.

In another embodiment, the “on” and “off” cycles, as describedpreviously, can cycle rapidly. For example, during a 30 minute period,the stimulation may be on for 3 seconds and off for 2 seconds during theentire 30 minute period.

In another embodiment, the patient can take a “stimulation holiday”. Inother words, stimulation can be further stopped for a time periodgreater than the “off” cycle to allow the muscle to recover. Greatlyincreasing the time period in which there is no stimulation also servesto avoid muscle fatigue and tolerance.

In another embodiment, stimulation parameters can be intermixed in anattempt to avoid muscle fatigue, habituation, and/or tolerance whilestill obtaining the desired level of LES function. For example,alternating short pulses can be intermixed with intermediate pulses tostimulate the LES, esophagus, upper esophageal sphincter, stomach,gastric fundus, or gastric cardia. The variation in stimuli received bythe muscle will assist in avoiding fatigue and tolerance.

In another embodiment, LES function can be normalized using the presentinvention without raising LES pressure above the mid-normal range. Thisis achieved by minimizing the energy delivered to the muscle to, but notbeyond, the point where the LES regains normal function. Less energydelivered results in less fatigue and tolerance.

In another embodiment, the stimulation parameters can be changed, suchas by modifying pulse width, frequency, amplitude, ramp rate, or theduty cycle, on a predefined periodic basis to avoid having the muscleshabituate to a known and repeated stimulation setting. In such anembodiment, a stimulator may locally store a plurality of differentstimulation parameters which are implemented in accordance with apredefined schedule. The stimulator may also store a single set ofstimulation parameters, each parameter having an acceptable range ofoperation, and then randomly implement a stimulation parameter boundedby the acceptable ranges of operation.

Electrode Configurations and Methods of Placing and Confirming thePlacement of Electrodes

In one embodiment, the therapeutic objectives described herein areachieved by at least one of a plurality of different electrodeconfigurations, as shown in FIG. 11 . It should be appreciated that, inone embodiment, the electrode placement, as shown, at least partlyenables the patient's LES function to normalize, post-stimulation,and/or the length of the patient's LES high pressure zone to increase orgastric pressure to decrease post-stimulation. The electrodeconfigurations described herein may be used in accordance with any ofthe stimulation parameters, system architectures, and sensing systemsdescribed herein.

Within the esophagus 1100, and more particularly the LES, a plurality ofdifferent electrode combinations can be used to achieve the therapeuticand operational objectives described herein. In one embodiment, a firstelectrode 1105 is placed proximate to the left lateral wall of theesophagus 1100 and operated in combination with a second electrodeplaced proximate to the right lateral wall 1110 of the esophagus 1100.In one embodiment, a first electrode 1105 is placed proximate to theleft lateral wall of the esophagus 1100 and operated in combination witha second electrode placed in the anterior proximal wall 1115 of theesophagus 1100. In one embodiment, a first electrode 1110 is placedproximate to the right lateral wall of the esophagus 1100 and operatedin combination with a second electrode placed in the anterior proximalwall 1115 of the esophagus 1100. In another embodiment, a firstelectrode 1105 is placed proximate to the left lateral wall of theesophagus 1100 and operated in combination with a second electrodeplaced in the anterior, distal wall 1120 of the esophagus 1100. In oneembodiment, a first electrode 1110 is placed proximate to the rightlateral wall of the esophagus 1100 and operated in combination with asecond electrode placed in the anterior, distal wall 1120 of theesophagus 1100. In another embodiment, a first electrode 1115 and asecond electrode 1120 are placed proximally and distally in the anteriorwall of the esophagus 1100. In another embodiment, more than one of theabove described combinations are used serially along the length of theesophagus 1100.

Referring to FIG. 12 , the electrodes 1205, 1210, 1215, 1220 can beplaced longitudinally or transversely or in any orientation relative tothe length of the esophagus 1200 and can be implemented in the sameexemplary combinations described in relation to FIG. 11 . It should beappreciated that not all of the electrodes shown in FIG. 11 need to beimplanted or operated concurrently. For example, to achieve any of theaforementioned therapeutic objectives, only one pair of electrodes, suchas 1105 and 1110 or 1115 and 1120 need be implanted and/or operatedconcurrently.

In another embodiment, shown in FIG. 13A, electrodes can be implanted inseries with two electrodes 1301, 1302 proximate to the left lateral wallof the esophagus 1300 and two electrodes 1303, 1304 proximate to theright lateral wall of the esophagus 1300. These electrodes can beactivated in various combinations, as described above, to provide forthe optimal normalization of LES pressure, with minimal energy deliveredto the tissue and minimal muscle fatigue or depletion ofneurotransmitter storages. It should be appreciated that, in oneembodiment, stimulation parameters (amplitude, timing of stimulationsession and switching of electrode configuration) will be set so as toactivate release of the appropriate neurotransmitter. Such parameterscan vary between patients due to surgical variation and physiologicalsensitivity. The electrode activation or implantation combinations caninclude electrodes 1301 and 1303, electrodes 1301 and 1302, electrodes1303 or 1304, electrodes 1301/1303 alternating with 1302/1304, andelectrodes 1301/1302 alternating with 1303/1304.

It should be appreciated that the length and surface area of theelectrode and the distance between the electrodes can affect the degreeand duration of the patient's post-stimulation normalization of LESfunction. It should further be appreciated that the length and surfacearea of the electrode can affect the current amplitude required toincrease the length of the LES high pressure zone or decrease gastricpressure post-stimulation.

In one embodiment, a patient is treated to achieve any one of theaforementioned therapeutic objectives by implanting the electrodes in a“linear” configuration. This is accomplished by implanting a firstelectrode axially along the length of the smooth muscle of the LES,shown as 1115 in FIG. 11 , and implanting a second electrode 1120 belowand substantially in alignment with the first electrode 1115. In variousembodiments, the bottom of the first electrode 1115 is separated fromthe top of the second electrode 1120 by a distance of no greater than 5cm, preferably no greater than 2 cm, and most preferably approximately 1cm. Each electrode is placed preferably more than 1 mm away from thevagal trunk. This electrode configuration is supplied with a stimulationpulse from a stimulator. The stimulation pulse may be delivered inaccordance with any of the aforementioned stimulation parameters. In oneembodiment, the stimulation pulse has a pulse amplitude no greater than15 mAmp and more preferably no greater than 8 mAmp. In one embodiment,the stimulation pulse has a pulse width of approximately 200 μsec and apulse repetition frequency of 20 Hz. A stimulator may further beconfigured to detect any of the aforementioned biological parameters,including length of the LES high pressure zone and gastric pressure. Inone embodiment, the length of the LES high pressure zone or gastricpressure is derived from a plurality of sensors adapted to generateimpedance measurements. In one embodiment, the length of the LES highpressure zone or gastric pressure is derived from piezoelectric sensorsor electrical activity based sensors.

In one embodiment, a patient is treated to achieve any one of theaforementioned therapeutic objectives by implanting the electrodes in a“parallel” configuration. Referring again to FIG. 11 , this isaccomplished by implanting a first electrode 1105 axially along thelength of the smooth muscle of the LES and implanting a second electrode1110 axially on the other side of the esophagus 1100, parallel to thefirst electrode 1105. In one embodiment, the distance between the firstelectrode 1105 and the second electrode 1110 is less than half thecircumference of the LES. The electrodes 1105, 1110 are implanted in theanterior portion of the LES, with preferably at least one electrodebeing in the right anterior portion of the LES (this places thestimulation as far as possible from the heart). Each electrode is placedpreferably more than 1 mm away from the vagal trunk. This electrodeconfiguration is supplied with a stimulation pulse from a stimulator.The stimulation pulse may be delivered in accordance with any of theaforementioned stimulation parameters. In one embodiment, thestimulation pulse has a pulse amplitude no greater than 15 mAmp and morepreferably no greater than 8 mAmp. In one embodiment, the stimulationpulse has a pulse width of approximately 200 μsec. A stimulator mayfurther be configured to detect any of the aforementioned biologicalparameters, including length of the LES high pressure zone or gastricpressure. In one embodiment, the length of the LES high pressure zone orgastric pressure is derived from a plurality of sensors adapted togenerate impedance measurements. In one embodiment, the length of theLES high pressure zone or gastric pressure is derived from piezoelectricsensors or electrical activity based sensors.

Referring now to FIG. 12 , in one embodiment, a patient is treated toachieve any one of the aforementioned therapeutic objectives byimplanting a first electrode 1215 transaxially across the length of thesmooth muscle of the LES and implanting a second electrode 1220substantially parallel to the first electrode and spaced apart from thefirst electrode 1215 by a distance of no greater than 5 cm. Thiselectrode configuration is supplied with a stimulation pulse from astimulator. The stimulation pulse may be delivered in accordance withany of the aforementioned stimulation parameters. In one embodiment, thestimulation pulse has a pulse amplitude no greater than 15 mAmp and morepreferably no greater than 8 mAmp. In one embodiment, the stimulationpulse has a pulse width of approximately 200 μsec. A stimulator mayfurther be configured to detect any of the aforementioned biologicalparameters, including length of the LES high pressure zone or gastricpressure. In one embodiment, the length of the LES high pressure zone orgastric pressure is derived from a plurality of sensors adapted togenerate impedance measurements. In one embodiment, the length of theLES high pressure zone or gastric pressure is derived from piezoelectricsensors or electrical activity based sensors.

In one embodiment, a patient is treated to achieve any one of theaforementioned therapeutic objectives by implanting a first electrodeand a second electrode in a configuration that concentrates currentdensity at two or fewer points close to each electrode. This electrodeconfiguration is supplied with a stimulation pulse from a stimulator.The stimulation pulse may be delivered in accordance with any of theaforementioned stimulation parameters. In one embodiment, thestimulation pulse has a pulse amplitude no greater than 15 mAmp and morepreferably no greater than 8 mAmp. In one embodiment, the stimulationpulse has a pulse width of approximately 200 μsec.

In one embodiment, a patient is treated to achieve any one of theaforementioned therapeutic objectives by implanting a first electrodeand a second electrode in a configuration that avoids distributingsubstantially all of the current density along the length of eachelectrode. This electrode configuration is supplied with a stimulationpulse from a stimulator. The stimulation pulse may be delivered inaccordance with any of the aforementioned stimulation parameters. In oneembodiment, the stimulation pulse has a pulse amplitude no greater than15 mAmp and more preferably no greater than 8 mAmp. In one embodiment,the stimulation pulse has a pulse width of approximately 200 μsec.

Variations in the stimulation and placement of electrodes also conveythe added benefit of avoiding muscle fatigue and tolerance, aspreviously discussed. For example, as shown in FIG. 12 , two pairs ofelectrodes, 1205/1210 and 1215/1220, can be implanted and stimulated inalternative succession. In one embodiment, the two pairs of electrodesreceive simultaneous stimulations with the same stimulation parameters.In another embodiment, the two pairs of electrodes receive sequentialstimulations with the same stimulation parameters. In anotherembodiment, the two pairs of electrodes receive simultaneousstimulations with different stimulation parameters. In anotherembodiment, the two pairs of electrodes receive sequential stimulationswith different stimulation parameters. Electrode placement can also bemanipulated to decrease muscle fatigue and tolerance. In one embodiment,the two pairs of electrodes are placed so that the distance between anyset of electrodes is less than two times the distance between the pairof electrodes, resulting in the stimulation from a set of electrodesstimulating less than 100% of the LES.

Preferably, during the implantation process, electrode configurationsare tested to verify that the proper configuration has been achieved. Inone embodiment, a catheter or endoscope configured to measure gastric orLES pressure in combination with a manometer is advanced to a locationproximate the implantation area while the newly implanted electrodes arestimulated. LES pressure is measured before, during, and/or afterstimulation. If the desired gastric pressure profile or LES pressureprofile in the high pressure zone is achieved, the implantation isdeemed successful and the testing may terminate. If the desired gastricpressure profile or LES pressure profile in the high pressure zone isnot achieved, the electrode configuration may be modified. Gastricand/or LES pressure testing is then repeated until the proper gastricpressure profile or LES pressure profile in the high pressure zone isachieved. Other sensed data, such as temperature, may also be used inthis testing process. It should be appreciated that the testing processcan be conducted separate from the implantation procedure. For example,patients can be tested with temporary electrodes, insertednon-invasively (nasogastrically, for example), and upon success can bedeemed suitable for implant.

In various embodiments, additional stimulating electrodes are implantedwithin the gastrointestinal tract to be used in conjunction with, or inplace of, the electrodes implanted in the LES detailed above. FIGS. 13Bthrough 13F illustrate various optional electrode configurations in thelower esophagus, LES, and gastric cardia for stimulation targeted toincrease the length of the LES high pressure zone. FIG. 13B is anillustration of the distal portion of an esophagus 1305 of a patientdepicting a first pair of electrodes 1330 implanted in the LES 1310 anda second pair of electrodes 1335 implanted in the gastric cardia 1325.FIG. 13C is an illustration of the distal portion of an esophagus of apatient depicting a first pair of electrodes 1330 implanted in the LES1310 and a second pair of electrodes 1333 implanted proximate the LES1310, in accordance with another embodiment of the presentspecification.

FIG. 13D is an illustration of the distal portion of an esophagus 1305of a patient depicting a pair of electrodes 1335 implanted in thegastric cardia 1325, in accordance with another embodiment of thepresent specification. FIG. 13E is an illustration of the distal portionof an esophagus 1305 of a patient depicting a pair of electrodes 1333implanted proximate the LES 1310, in accordance with one embodiment ofthe present specification;

FIG. 13F is an illustration of the distal portion of an esophagus 1305of a patient depicting a first pair of electrodes 1335 implanted in thegastric cardia 1325 and a second pair of electrodes 1333 implantedproximate the LES 1310, in accordance with another embodiment of thepresent specification. FIG. 13G is an illustration of the distal portionof an esophagus 1305 of a patient depicting a first pair of electrodes1330 implanted in the LES 1310, a second pair of electrodes 1335implanted in the gastric cardia 1325, and a third pair of electrodes1333 implanted proximate the LES 1310, in accordance with one embodimentof the present specification.

In various embodiments, any of the electrode configurations can be usedwith any methodology disclosed in the present specification to enhancethe length of the LES high pressure zone to achieve any of thetherapeutic goals listed above.

FIGS. 13H through 13M illustrate various optional electrodeconfigurations in the lower esophagus, LES, and gastric fundus targetedto increase the receptive relaxation response of the stomach anddecrease gastric pressure. FIG. 13H is an illustration of the distalportion of an esophagus 1345 and a stomach 1355 of a patient depicting afirst pair of electrodes 1370 implanted in the LES 1350 and a secondpair of electrodes 1375 implanted in the gastric fundus 1365. FIG. 13Iis an illustration of the distal portion of an esophagus 1345 and astomach 1355 of a patient depicting a first pair of electrodes 1370implanted in the LES 1350 and a second pair of electrodes 1373 implantedproximate the LES 1350, in accordance with another embodiment of thepresent specification.

FIG. 13J is an illustration of the distal portion of an esophagus 1345and a stomach 1355 of a patient depicting a pair of electrodes 1375implanted in the gastric fundus 1365, in accordance with anotherembodiment of the present specification. FIG. 13K is an illustration ofthe distal portion of an esophagus 1345 and a stomach 1355 of a patientdepicting a pair of electrodes 1373 implanted proximate the LES 1350, inaccordance with one embodiment of the present specification.

FIG. 13L is an illustration of the distal portion of an esophagus 1345and a stomach 1355 of a patient depicting a first pair of electrodes1375 implanted in the gastric fundus 1365 and a second pair ofelectrodes 1373 implanted proximate the LES 1350, in accordance withanother embodiment of the present specification. FIG. 13M is anillustration of the distal portion of an esophagus 1345 and a stomach1355 of a patient depicting a first pair of electrodes 1370 implanted inthe LES 1350, a second pair of electrodes 1375 implanted in the gastricfundus 1365, and a third pair of electrodes 1373 implanted proximate theLES 1350, in accordance with one embodiment of the presentspecification.

In various embodiments, any of the electrode configurations can be usedwith any methodology disclosed in the present specification to modulatefundus tone and decrease gastric pressure to achieve any of thetherapeutic goals listed above.

Stimulator Energy Storage and Sensing Systems

Nan-Sensing Active Implantable Medical Devices

The embodiments disclosed herein achieve one or more of the above listedtherapeutic objectives using stimulation systems that are energyefficient and do not require sensing systems to identify wet swallows,bolus propagation, or patient symptom changes, thereby enabling a lesscomplex, smaller stimulation device which can more readily be implantedusing endoscopic, laparoscopic or stereotactic techniques. The disclosedstimulation methods permit a natural wet or bolus swallow to overridethe electrically induced stimulation effect, thereby allowing for anatural wet or bolus swallow without having to change, terminate, ormodify the stimulation parameters.

It should be appreciated that, in one embodiment, the stimulation devicereceives energy from a remote energy source that is wirelesslytransmitting ultrasound or RF based energy to the stimulation device,which comprises receivers capable of receiving the energy and directingthe energy toward stimulating one or more electrodes. It should furtherbe appreciated that the device may be voltage driven or current driven,depending upon the chosen embodiment.

It should be appreciated that, in another embodiment, the stimulationdevice is a macrostimulator that receives energy from a local energysource, such as a battery, and directs the energy toward stimulating oneor more electrodes. It should further be appreciated that the device maybe voltage driven or current driven, depending upon the chosenembodiment.

By not requiring sensing systems that identify wet swallows, boluspropagation, or patient symptom changes, at least certain embodimentscan operate with increased reliability and also be smaller in size. Thesmaller device size results in increased patient comfort, allows forplacement (implantation) in the patient in more appropriate and/orconvenient locations in the patient's anatomy, and allows the use ofdifferent surgical techniques for implantation (laparoscopic,endoscopic) and/or smaller incisions, which are less invasive, causeless trauma, cause less tissue damage, and have less risk of infection.The small size can also allow placement of a larger number of devices soas to provide redundancy, improved clinical efficacy, durability andreliability.

In addition to the absence of certain components which, conventionally,were required to be part of such an electrical stimulation system,embodiments of the present specification can achieve the above-listedtherapeutic objectives using stimulation systems that operate at lowenergy level, such as at or below 20 Hz with a current of at or below 8mAmp, preferably 3 mAmp, and a pulse width of 200 μsec.

As a result of the operative energy range, the following benefits can beachieved: a) a wider range of electrode designs, styles, or materialsmay be implemented, b) the need to use special protective coatings onelectrodes, such as iridium oxide, or titanium nitride, while stillmaintaining electrode surface areas below 5 mm², is eliminated, c) onehas the option of using small electrode surface areas, preferably belowa predefined size with coatings to increase the effective surface area,such as iridium oxide, or titanium nitride, d) one can operate inwireless energy ranges that are within regulatory guidelines and safetylimits and do not pose interference issues, such as a RF field strengthbelow a predefined limit and ultrasound field strength below apredefined limit.

It should further be appreciated that the presently disclosed systemscan be implemented using a variety of surgical techniques, includinglaparoscopic and endoscopic techniques. In one embodiment, alaparoscopically implanted device comprises a battery providing localenergy storage and only optionally receives energy through wirelesstransfer, such as RF or ultrasound. In such an embodiment, the devicestimulates at a higher amperage for shorter periods of time, relative toembodiments without local energy storage, thereby allowing for longeroff cycles, lower duty cycles, and better battery efficiency. In oneembodiment, an endoscopically implanted device may or may not comprise alocal energy storage device but does comprise a wireless receiver toreceive energy wirelessly transmitted from an external energy source andtransmission device. In such an embodiment, this device stimulates at alower energy setting for longer on cycles and shorter off cycles,relative to the embodiment with local energy storage, thereby having agreater duty cycle than a laparoscopic implant.

The stimulators of the present specification, when properly programmedin accordance with the stimulation parameters described herein andassociated with the appropriate electrode configurations, exhibit a highdegree of energy efficiency. In one embodiment, the electricalstimulation device initiates electrical stimulation based upon aninternal clock or a patient activated trigger. Electrical stimulationthen continues for a pre-set or predefined period of time. Referencing a24 hour period of time, the preset or predefined period of time may beequal to an “on” time period that is less than or equal to 24 hours, 12hours, 1 second, or any increment therein. Upon completion of thatpredefined period of time, the internal clock then causes the electricalstimulation device to terminate electrical stimulation.

It should be appreciated that any activation by an internal clock can beconfigured to cycle daily or a few times daily or be synchronized tomeal times, as signaled manually by a patient. It should further beappreciated that the timing of meal times or other physiologicallyrelevant events can be saved and/or learned, thereby enabling the deviceto default to standard initiation of stimulation time or termination ofstimulation time based upon past data gathered. The setting ofstimulation times may be set by a physician, based on an interview witha patient or based on the detection of eating using pH sensing or someother automated eating detection mechanism. In one embodiment,stimulation is initiated in advance of a predefined meal time to achievean increase in LES tone before the patient eats. For example, if apatient's predefined meal time is 2 pm, then stimulation is set toinitiate in advance of 2 pm, such as 1:30 pm. If the patient thenreports symptoms between 4-6 pm, then, in the future, stimulation may bereinitiated at 3 pm. If a patient's predefined meal time is 12 pm, thenset stimulation is set to initiate in advance of 12 pm, such as 11:30am. If the patient then reports symptoms between 2-4 pm, stimulation maybe reinitiated at 1 pm.

In another embodiment, the electrical stimulation device initiateselectrical stimulation based upon an internal clock or a patientactivated trigger. Electrical stimulation then continues for a pre-setor predefined period of time. Upon completion of that predefined periodof time, the internal clock then causes the electrical stimulationdevice to terminate electrical stimulation. This ratio of the predefinedperiod of stimulation relative to the time where electrical stimulationis terminated is less than 100%, up to a maximum duty cycle, such as70%, 75%, 80%, 85%, 90%, 95%, or any increment therein.

In another embodiment, the electrical stimulation device initiateselectrical stimulation based upon an internal clock or a patientactivated trigger. Electrical stimulation then continues for a pre-setor predefined period of time. The pre-set or predefined period of timemay be equal to a time period that is up to a maximum “on” period, suchas 12 hours, during which the device may be continually operating. Uponcompletion of that predefined period of time, the internal clock thencauses the electrical stimulation device to terminate electricalstimulation.

In another embodiment, the electrical stimulation device initiateselectrical stimulation based upon an internal clock or a patientactivated trigger. Electrical stimulation then continues for a pre-setor predefined period of time. The pre-set or predefined period of timemay be equal to a time period that is up to a maximum “off” period, suchas 12 hours, during which the device is not operating. Upon completionof that predefined period of time, the internal clock then causes theelectrical stimulation device to restart electrical stimulation.

In another embodiment, the electrical stimulation device initiateselectrical stimulation based upon an internal clock or a patientactivated trigger. Electrical stimulation then continues for a pre-setor predefined period of time. The pre-set or predefined period of timemay be equal to a time period that is less than the time required to seea visible change in the length of the LES high pressure zone or gastricpressure. Upon completion of that predefined period of time, theinternal clock then causes the electrical stimulation device toterminate electrical stimulation. The desired increase in the length ofthe LES high pressure zone or decrease in gastric pressure occurspost-stimulation, followed by a decrease in high pressure zone length oran increase in gastric pressure which still remains beyond apre-stimulation state after a period of >1 hour.

It should be appreciated that other stimulation protocols, which resultin the desired effect of operating for less than 100% of duty cycle andwhich have a pre-set or predefined period of non-stimulation, can beachieved using combinations of turning on and off subsets of electrodesat different times. For example, one may turn a first subset ofelectrodes on, turn a second subset of electrodes on, then turn allelectrodes off, followed by turning a second subset of electrodes on,turning a first subset of electrodes on, and then all electrodes offagain.

Sensing Active Implantable Medical Devices

It should be appreciated that the systems of the present specificationcan be optionally operated in combination with sensing systems capableof sensing physiological events, such as eating, swallowing, a boluspropagating through the esophagus, muscle fatigue, pH level, esophagealpressure, tissue impedance, length of LES high pressure zone, LEStone/pressure, gastric pressure, patient position, sleep state, or awakestate. In such a case, a physiological event can be used to modify thestimulation schedule by, for example, extending the stimulation timeperiod based upon sensed pH level, eating, swallowing, or a boluspropagating through the esophagus or, for example, terminating thestimulation period before the preset time period expires based uponsensed muscle fatigue.

It should also be appreciated that the present invention can be drivenby, and fully triggered by, sensing systems capable of sensingphysiological events, such as eating, swallowing, a bolus propagatingthrough the esophagus, muscle fatigue, pH level, esophageal pressure,tissue impedance, length of LES high pressure zone, LES tone/pressure,gastric pressure, patient position, sleep state, or awake state. In sucha case, a physiological event can be used to initiate the stimulationschedule.

By operating the stimulation system less than 100% duty cycle and havingthe stimulation device be off during preselected periods, the presentlydisclosed stimulation system uses less energy than prior art devices.Accordingly, the stimulation systems disclosed herein can effectivelyoperate to achieve the above-listed therapeutic objectives using anenergy source local to the stimulator that a) does not include abattery, b) includes a small battery capable of being recharged from anexternal energy source, c) only includes a capacitor and, morespecifically, a capacitor having a rating of less than 0.1 Farads or d)only includes a battery that is not rechargeable.

In one embodiment, a stimulator uses a remote data sensor forautomatically adjusting parameters. The stimulator comprises stimulatingcircuitry contained within a housing that includes a power source, meansfor delivering stimulation, a receiver to collect data from a remotesensor and a control unit that analyzes the data received from thereceiver and adjusts the stimulation parameters based on a plurality ofstored programmatic instructions and the received data. The means forstimulation may include any form of leaded or a leadless device. Thestimulator element would preferably be implanted either under the skin,in cases where the stimulator comprises a macrostimulator internal pulsegenerator (IPG), or close to the stimulation area, in cases where thestimulator comprises a microstimulator. The stimulator can also comprisea plurality of separate units, in separate housings, including, forexample, an external control unit and receiver and an implantablestimulator, similar to a passive microstimulator.

The stimulator is in wireless or wired data communication with one ormore sensor elements. The sensor elements are implanted in an area thatallows the sensor to collect physiological data relevant to thecontrolling the operation of the stimulator. Each sensor elementincludes means for sensing the required physiological function and meansfor transmitting the data to the control unit. In one embodiment, thesensor element comprises a capsule adapted to measure physiological pHand transmit pH data from within the lumen of the esophagus to animplantable stimulator device. In another embodiment, the sensor elementcomprises a pH sensor located within a nasogastric tube and means fortransmitting the pH data to an implanted control unit. In anotherembodiment, the stimulator comprises electrodes implanted in the LESthat are wired to an implantable IPG, which is in data communicationwith a pH measuring element, such as but not limited to a pH capsule ora catheter based device, that is transmitting pH data to the device viauni-directional or bi-directional communication.

In another embodiment, the stimulator/sensing system disclosed hereincan locally store a plurality of programmatic instructions that, whenexecuted by circuitry within the IPG, uses data received from a capsuleto automatically refine stimulation parameters within a pre-definedrange of boundaries. The data may be continuously streamed from thesensing capsule to the IPG and may be subject to continuous monitoringand processing. The data may comprise any one of pH data, gastricpressure data, LES pressure data, temperature, impedance, incline, orother physiological data.

Referring to FIG. 14 , a patient 1400 has implanted within his tissue astimulator 1415, as further described below. The stimulator 1415 isadapted to dynamically communicate with a temporary sensor 1410, asfurther described below, which may be located inside the patient's GIlumen. The implanted stimulator 1415 comprises stimulator circuitry andmemory having programmatic instructions that, when executed, perform thefollowing functions: transmit an interrogating signal designed to elicitor cause a transmission of sensed data from the temporary sensor 1410 orreceive a transmitted signal comprising sensed data from the temporarysensor 1415 and process the sensed data to modify stimulationparameters, such as frequency, duration, amplitude, or timing.Optionally, the stimulator 1415 may also analyze the received senseddata signal to determine if the data is reliable. The implantedstimulator 1415 is adapted to only modify stimulation parameters orotherwise engage in a processing routine adapted to use the sensed datato determine how the simulation parameters should be modified when itsenses and receives the sensed data. Optionally, the implantedstimulator 1415 is adapted to modify stimulation parameters or otherwiseengage in a processing routine adapted to use the sensed data incombination with patient data inputted into an external device todetermine how the simulation parameters should be modified.

For example, where a meal event, sleeping event, or other event whichmay cause, be related to, or be associated with a GERD event, isexpected to occur at a specific time during the day (either becausepreviously sensed data has determined a pattern indicating the existenceof such an event or because patient data expressly indicates that suchan event should be expected), stimulation parameters may be modified orotherwise established in order to provide the requisite level, degree oramount of stimulation before the anticipated event, such as 5 minutes,10 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes,or some increment therein. The determination of stimulation parameters,including start time, end time, pulse frequency, duration, ramp rate,duty cycle, and/or amplitude, can be determined independent of thepatient's immediate physiological state and not causally related to thepatient's existing condition. Rather, historical data patterns fromsensors, including LES high pressure zone length data, gastric pressuredata, LES pressure data, temperature, impedance, incline, or otherphysiological data, can be used to define the GERD profile of a patient,namely when, in the course of a day, a patient is likely to experience aGERD event, and then used to proactively normalize LES function inadvance of the GERD event. To properly generate and mine data patterns,it is preferable to capture both the magnitude of the physiological data(i.e. pH<4), the duration (for one hour), and the timing (around 1 pm).It is further preferable to associate different physiological data witheach other to see if a predictive pattern may exist between data setsand to further correlate that data with the patient's own reporting ofpain, discomfort, acid reflux, or other sensations to better determinewhen a GERD event is likely to occur in a day.

In one embodiment, the implanted stimulator 1415 is configured to checkthe reliability of the data by processing it to determine whether thedata is indicative of the sensor being in an improper location. In oneembodiment, wherein the temporary sensor is a capsule measuring pH dataintended to measure esophageal pH, such a determination process may beconducted by: a) monitoring the received pH data over a predefinedperiod of time to determine if it is indicative of a high pHenvironment, such as the patient's stomach as opposed to the esophagus,b) monitoring the received data signal, such as an RF signal, over apredefined period of time to determine if the signal strength hassignificantly changed or modified, indicating a change in physicallocation, or c) monitoring a received accelerometer or inclinometer datasignal from the pH capsule, over a predefined period of time, todetermine if the capsule is in a proper physical orientation. Dependingon the reliability check, the implanted stimulator 1415 may use, ordiscard, the sensed data. If no reliable data is received by theimplanted stimulator 1415, it does not modify stimulation parameters orotherwise engage in a processing routine adapted to use the sensed datato determine how the simulation parameters should be modified. Ifreliable data is received by the implanted stimulator 1415, it modifiesstimulation parameters or otherwise engages in a processing routineadapted to use the sensed data to determine how the simulationparameters should be modified.

In one embodiment, the temporary sensor 1402 stores the sensed andtransmitted data and transmits the stored data to an external readingdevice. It should be appreciated that the previously discussed methodsfor using sensed data, whether from a temporary sensor or permanentlyimplanted sensor, may be performed by an external device. For example,in one embodiment, an external device wirelessly receives sensed dataand uses the sensed data to determine a pattern indicative of when aGERD event is likely to be experienced by a patient. Any patternanalysis method known to persons of ordinary skill in the art may beused. The data may include some or all of the sense data, externallyinputted patient data, or a combination thereof. As discussed above, theexternal device would use the data to determine the time(s) of day whena patient typically experiences a GERD event and the appropriatestimulation parameters required to normalize LES function prior to suchevent. In one embodiment, the requisite stimulation parameters aredetermined by examining historical GERD events in relation tostimulation parameters that had been implemented and modifying thestimulation parameters to increase or decrease the magnitude or durationof the stimulation accordingly. Additionally, in one embodiment, theimplanted stimulator 1415 stores the sensed data and data indicative ofhow stimulation parameters, such as frequency, duration, amplitude, ortiming, were modified based on the sensed data, and transmits the storeddata to an external reading device.

Referring to FIG. 15 , in one embodiment, the process 1500 implementedby the stimulator system comprises collecting 1505 pH data periodicallyor continuously over a predefined period, such as 1, 2, 6, 12, 24, 36,48, or 60 hours, or any time increment in between. Circuitry within thestimulator analyzes the pH data 1510 to determine if, within thepredefined period, such as 24 hours, pH is less than a predefined value,such as 4, for a percentage of time higher than a threshold value, suchas 1, 2, 3, 4, 5, 10, 15, or 20 hours, or any increment therein 1515.The processor may analyze pH data 1510 by integrating periods in whichthe pH is less than the predefined value compared with stimulation timesand separately integrate periods with stimulation in a most recent timeperiod (i.e. last 6 hours) to periods without stimulation in the mostrecent time period.

If the percentage of time with the pH less than the predefined valuewithin a predefined period is lower than a threshold value, such as 1percent or lower 1520, then the circuitry may adjust stimulationparameters 1525 so as to reduce the timing, frequency, or size of thestimulation doses. In one embodiment, the circuitry decreases dailystimulations or amplitudes by a discrete amount, such as 1 mAmp. In oneembodiment, the system may not reduce the timing, frequency, or size ofthe stimulation doses below a minimum dose.

If the percentage of time with the pH less than the predefined valuewithin a predefined period is greater than a threshold value, such as 5percent or higher 1515, then the circuitry may further analyze 1530whether there were more periods with pH being greater than the thresholdvalue during which there was no stimulation than with stimulation. Ifthere were more periods with pH being greater than the threshold valueduring which there was no stimulation than with stimulation, thecircuitry may increase the number of daily stimulations by a discreteamount, such as by 1 1535 or the duty cycle or length of a givenstimulation session or duration by a discrete amount, such as 1 minute.By doing so, the system assumes the amount of energy delivered perstimulation is sufficient, but there simply were not enough stimulationevents in a day, or the stimulation was not long enough. If there weremore periods with pH being greater than the threshold value during whichthere was stimulation than with no stimulation, the circuitry increasesthe amplitudes of stimulations by a discrete amount, such as by 1 mAmp1540. By doing so, the system assumes the amount of energy delivered perstimulation was not sufficient and therefore increases the energydelivered per stimulation. In one embodiment, the system may notincrease the timing, frequency, or size of the stimulation doses above amaximum dose.

In general, if the percentage of time within a predefined period duringwhich pH is less than a threshold value, such as 4, is higher than anupper value, such as 5%, then the stimulation parameters will beadjusted so as to increase dose. Also, if the percentage of time withina predefined period during which pH is less than a threshold value, suchas 4, is lower than a lower value, such as 1%, then the stimulationparameters may be adjusted so as to reduce dose. The decreasing andincreasing of dose will be done based on the temporal behavior of the pHvalues. It should be appreciated that doses may be incremented by anyamount. It should further be appreciated that doses can be effectivelydecreased or increased by increasing one parameter while reducinganother parameter so that the total energy is increased, reduced, orunchanged. Finally, it should be appreciated that all modifiableparameters will be bounded, on at least one of the maximum or minimumboundary, by a range defined by a healthcare provider.

In another embodiment, the operation of the system is augmented withother sensed data. Where the system is being used to stimulate the LESor fundus or to treat GERD, pH sensor data can be augmented withaccelerometer and/or inclinometer data. The accelerometer orinclinometer sensor(s) could be located within the implantable device orin another device on or inside the patient body. This additional datacan enable the control unit algorithm to assess patient modes (e.g.,sleep, exercise, etc) and thereby to improve the tuning of stimulationparameters for a specific patient, thereby improving device efficacyand/or efficiency. Additional sources of information may include, butnot be limited to, pressure measurement or an impedance measurement by acapsule or an eating detection mechanism using one or more sources suchas impedance or other electrical or electromechanical measurement fromwithin the tissue or from the lumen. These additional sources ofinformation can further be used by the control unit to adjust thestimulation dose and other parameters and other functions of theimplantable device. It should be appreciated that any of theaforementioned data may be used individually or in combination to modifythe operation of the system and, in particular, to determine howstimulation parameters should be modified to address an anticipatedpatient GERD event.

In one embodiment, the system logs the sensed and computed data anddownloads the data to an external device for viewing and analyzing by amedical professional or a technician. By permitting on-demand or batchdownloading, the system can eliminate the need for the patient to carryan external receiver during pH-sensing, thereby improving the useexperience of the patient and potentially improving compliance andallowing for longer measurement periods. The system can download dataautomatically and without any requirement for user intervention, such aswhen an appropriately calibrated external device comes within a datacommunication area of the implanted device, or semi-automatically, suchas when initiated by the implantable device when the implantable deviceis in proximity (communication distance) of the external device and theuser has provided a password or other indication of approval via theexternal wireless interrogation device.

It should be appreciated that the external device receiving the sensedor computed data could be located at the healthcare provider's locationor at the patient's home. If captured at the patient's home, the datacould be automatically sent to the clinic for physician review and/orapproval of suggested parameter changes via any communication medium,including Internet, Ethernet network, PSTN telephony, cellular,Bluetooth, 802.11, or other forms of wired or wireless communication.The transmitted data preferably contain the measured values, therecommended stimulation parameters adjustments, or both. Similarly, thephysician approval, or physician suggested parameter changes, could besent back to the external device located at the patient's home which, inturn, transmits appropriate commands to the implanted device, when thetwo devices are in proximity, to initiate the suggested parameterchanges.

In another embodiment, the system monitors sensor, such as capsule,failure. If the sensor fails an internal diagnostic test, a failure oralert signal is transmitted to the implanted control unit, or theimplanted control unit itself logs a failed attempt to communicate with,or obtain uncorrupted data from, the sensor. The control unit thentransmits that failure or alert signal data to the external device and,in turn, to the healthcare provider, as described above, therebyalerting a healthcare provider that the patient needs to return to havethe sensor fixed or another sensor implanted.

In another embodiment, the system is capable of recognizing andregistering a plurality of different sensing devices, such as capsules,and re-initiate newly implanted sensors as required to ensure continuousor substantially continuous measurement. For example, the stimulator canbe implanted for a long period of time, such as several months or years,and for a shorter period of time, such as once per annum, a sensor isimplanted. The stimulator registers the new sensor and automaticallyadjusts the new sensor for operation in the particular anatomicalregion, such as the esophagus.

In addition to failing, sensors may migrate out of the implantedanatomical region. For example, where a sensor, such as a capsule, hasbeen implanted into a patient's esophagus but has migrated to thestomach, the physical location of the sensor can be derived by examiningthe sensed data. For example, where a pH capsule has moved from theesophagus to the stomach, the capsule will likely transmit dataindicative of extensively long periods during which the pH is highlyacidic. In that case, the stimulator system can assume the capsule hasmigrated, report this failure to an external device, and ignore futuredata being transmitted from the capsule or record the data but not relyupon it for parameter setting. Similarly, the stimulation system mayregister a weaker or changed signal, indicative of a sensor moving adistance away from the recording device.

The presently disclosed stimulator system may further comprise areceiving antenna integrated into a stimulator system, which may be usedfor energy transfer to the stimulator system and communication to andfrom the device. The close proximity between the stimulator,particularly a miniature device, and a sensor, such as the pH capsule,can be used to achieve communication efficiency and increase durabilitythrough a miniature antenna in the stimulator that can accept data fromthe pH capsule. The close distance can effectively reduce powerrequirements and enables typical low frequency inductively coupledtelemetry for transmission through titanium via coils; as well as highfrequency RF communication such as MICS or IMS bands via monopole,dipole, or fractal electric field antennas. The communication distancecan be further reduced by enabling anchoring of the pH capsule ornasogastric tube to the implanted control unit. This can be facilitatedby, for example, a magnetic force between the two units caused by amagnet in both units or a magnet in one unit and a ferrous metal in theother.

One of ordinary skill in the art would appreciate that other means forcommunication can be used that will take advantage of the closeproximity between the stimulating electrodes and the sensing device,such as a pH capsule, even when the control unit is farther away,thereby allowing for a significant reduction in the power consumptionand improvement of reliability of communication. The stimulatingelectrodes in that embodiment would serve as receiving antennas and alsosimplify the design of the control unit, thereby avoiding the need for areceiving coil, antenna or other electromagnetic receiving means.

Bi-directional communication between the control unit and the sensorunit can be implemented as part of the system to allow, for example,calibration or activation of specific actions such as additionalmeasurements, determination of measurements to be taken, determinationof measurement times, local stimulation by the sensor unit, among othervariables. The sensor unit can also be used to not only transmit thesensed data, but also to transmit energy for charging and powering thecontrol unit and the stimulating device. For example, pH capsules thatfurther acts as an energy recharging source can be periodicallyimplanted, as required, to deliver energy to the control unit or amicro-stimulator in addition to actually sensing pH data.

Patient Selection Methods

In one embodiment, a person is permitted to practice the treatmentsystems and methods disclosed herein and, in particular, to have anembodiment of the electrical stimulation systems disclosed hereinimplanted into him or her only if the person passes a plurality ofscreening or filtering steps.

In one embodiment, a plurality of physiological measurements are takenof the patient and used to determine whether the patient maytherapeutically benefit from the electrical stimulation treatmentsystems and methods disclosed herein. LES high pressure zone lengthdata, LES pressure data, gastric pressure data, and/or pH data iscollected from the patient. For example, pH measurements are obtainedover a period of time, such as 4, 8, 12, 16, 20, or 24 hours or someincrement therein. The amount of time within the predefined measurementperiod during which the pH measurement is above a predefined thresholdindicative of acid exposure, such as a pH of 4, is calculated. Thenumber of acid exposure events occurring for more than a predefinedperiod of time, such as more than 1, 3, 10, 15, or 20 minutes, or anyincrement therein, is determined. The total time for each acid exposureevent lasting more than the predefined period of time, i.e. 3 minutes,referred to as a long event, is then summed. If that total time exceedsa predefined threshold, such as 5 minutes to 240 minutes or anyincrement therein, it may be concluded that the patient wouldtherapeutically benefit from the electrical stimulation treatmentsystems and methods disclosed herein. For example, if a patient has 4events of acid exposure lasting 1, 4, 5 and 6 minutes and the predefinedthreshold is 3 minutes, the total time would be equal to 15 minutes(4+5+6). If the total time threshold is 10 minutes, then the patient canbe categorized as an individual who would benefit from the electricalstimulation treatment systems and methods disclosed herein.

Another physiological measurement that may be used to select eligiblepatients is LES end expiratory pressure (LES-EEP). In one embodiment, apatient's LES-EEP is measured and collected during resting time, e.g. noswallow for at least 30 seconds, and then compared to at least onethreshold. For example, the value of the LES-EEP should be below anormal value threshold, such as 10-20 mmHg, preferably 12-18 mmHg, andmore preferably 15 mmHg, in order for the patient to qualify fortreatment. In another embodiment, a patient's LES-EEP is measured andcollected during resting time, e.g. no swallow for at least 30 seconds,and then compared to a range of pressure values, e.g. to two differentthreshold values. For example, the value of the LES-EEP should be abovea lower threshold, which is indicative of the LES having some basefunctionality, such as 0 mmHg to 3 mmHg or any increment therein andbelow an upper threshold, such as 8 mmHg to 10 mmHg or any incrementtherein.

Another physiological measurement that may be used to select eligiblepatients is the rate of transient LES relaxation events (tLESR).Patients with higher rates of tLESRs which constitute a portion of theiracid exposure time above a predefined threshold may benefit less fromtreatment than patients with lower rates of tLESRs constituting aportion of their acid exposure time above a predefined threshold. In oneembodiment, a patient's tLESR rate is determined over a period of time,such as 24 hours or less. The tLESR rate is determined by recording thenumber and duration of acid exposure events, as described above, andthen calculating the number of acid exposure events shorter than apredefined time period, such as shorter a total time threshold, asdefined above, shorter than 5 minutes, shorter than 10 seconds orshorter than any increment therein, generally referred to as a shortevent. The number of such short events per period is then compared to aninclusion threshold, such as a range of 3-50, preferably 5-20. If thenumber of short events is below the range, the patient may not qualifyfor treatment or may qualify for a different stimulation regimen thatcan be programmed into the stimulator.

In another embodiment, a patient's acid exposure times are recorded andthen compared to the timing of patient's reported reflux symptoms. Thedegree of temporal correlation between the acid exposure times andreported symptoms is then determined. Patients with a degree ofcorrelation above a predefined threshold would be eligible for treatmentwhile those below the predefined threshold would not be.

In another embodiment, it is determined whether a patient maytherapeutically benefit from the electrical stimulation treatmentsystems and methods disclosed herein by temporarily stimulating thepatient for a period of time, such as less than one week, using anon-permanent implanted stimulator to evaluate the patient'sphysiological response to stimulation and predict the patient's likelyphysiological response to a permanent stimulator. In one embodiment, thetemporary stimulation is delivered using a temporary pacing leadendoscopically implanted in the patient's LES and connected to anexternal stimulator, which is either a non-portable system or a portablebattery-operated device. The temporary stimulation system deliversperiodic stimulations over a period of time, from 30 minutes to twoweeks or more, during which the patient's symptoms, acid exposureevents, and physiological response are recorded and correlations betweenthe three are determined. The temporary stimulation data can then beused to determine the likely timings of GERD events and the requiredstimulation parameters to proactively normalize the patient's LES inadvance of the GERD events, as previously discussed. Once the temporarystimulation period is complete, the electrode can be removed and adecision can be made regarding whether the patient would therapeuticallybenefit from a permanent implant based, for example, on the patient'sphysiological response to the temporary stimulation, improvement insymptoms, normalization of pH levels, normalization or increase in LEShigh pressure zone length, decrease in gastric pressure, and/ornormalization of LES pressure.

In one embodiment, the temporary stimulator is in the shape of a smallcapsule-like device that is self-contained and includes all requiredcomponents for stimulation including a power source or a receiver thatallows power to be received wirelessly from outside the body and one ormore electrodes. The device is adapted to stimulate the LES or gastrictissue. The device also includes an anchoring component, such as a hook,corkscrew, rivet, or any other such mechanism, which temporarilyconnects it to the LES or gastric wall. The capsule is implanted throughan endoscopic or catheterization procedure to the LES or gastric wall.Such a capsule is expected to remain attached to the LES or gastric wallfor a period of one day to two weeks or longer and then detach by itselfand leave the body naturally. Further the device can include a sensorfor detecting when it is attached to the wall, which will only stimulatewhen it detects that the device is still attached to the LES or gastricwall. Additionally the device may include wireless communication toallow telemetry and/or commands to be delivered from outside the body.The capsule can additionally include pH measurement, manometrymeasurement or other physiological measurement devices or sensors sothat the short term efficacy of the stimulation can be more easilyevaluated. Additional standard measurements can be made as needed forobtaining more information.

It should be appreciated that any form of temporary stimulator could beused. For example, a stimulator can include a) a plurality ofimplantable leads adapted to be temporarily implanted into the LES orgastric tissue through endoscopy, laparoscopy or other minimallyinvasive methods and further adapted to deliver stimulation to the LESor gastric fundus, b) a housing which includes a control unit andcircuitry for generating electrical stimulation where the housing isadapted to be temporarily implantable and/or be integrated with theleads such that the housing itself can deliver stimulation or externallylocated and wired to the leads without being implantable and/or c) anadditional unit capable of recording the physiological data, stimulationdata, and various patient inputs (symptoms, eating, sleeping events,etc.) and adapted to be used for turning stimulation on or off.Optionally, the additional unit is controlled by a physician andwirelessly programmable using a physician's computer system. Optionally,the stimulator can also be configured to include sensors or communicatewith sensors that measure the aforementioned physiological measures.

Other approaches for selecting patients based on physiological dataand/or temporary stimulation can also be implemented. It should be clearto person skilled in the art that the above selection methods could beintegrated in various ways to result in an optimal selection ofpatients. For example one integrated method can be used to screenpatients by qualifying candidates according to pH long events, themanometry value of LES-EEP, or the number of short events, or anycombination thereof. Additionally, a combination of the measures can beused such as dividing the total length of long events by the rate ofshort events and comparing this value against a properly adjustedthreshold, such that patients with a ratio above the threshold areincluded and others are excluded. Once qualified, the patient canundergo the permanent implant procedure or undergo the temporarystimulation process to further qualify the patient.

Physician Diagnostic and Programming Systems and Methods

Different patients may require different therapeutic regimens, dependingupon implant depth, anatomical variations, treatment objectives, andseverity of the disease condition. Each patient has a different baselineLES high pressure zone length and baseline gastric pressure anddifferent responses to stimulation (due to expected variability insphincter and gastric muscle condition and also in the implantlocation). Furthermore, changes to the patient's anatomy, for examplearising from normal healing after implantation, chronic stimulation orage, can also change the optimal stimulation dosage. Accordingly, it ispreferred for a patient to first undergo a diagnostic process todetermine whether, and to what extent, the patient can be treated by oneof a plurality of therapeutic processes, as further described below. Itis also preferred for a patient to periodically visit a physician tohave the efficacy of the stimulation system checked, optimized, andpossibly reprogrammed, as provided below.

In one embodiment, because the goal is to keep the stomach at a gastricpressure or function which eliminates or greatly reduces the chances foracid exposure, it is unnecessary for the muscle to always have lowpressure but, rather, it is desirable to have (1) some average pressuresustained at all times with a certain permitted range of variabilityaround it and a maximum pressure that the stomach will never be, or willrarely be, above or (2) some average function sustained at all timeswith a certain permitted range of variability around it and a minimalfunction that the LES will never be, or will rarely be, below or acombination thereof. Continuous non-stop stimulation is not optimalbecause the acute response of enhanced pressure may diminish over timedue to neuromuscular tolerance or muscle fatigue. Furthermore, a simple“on-off” regime during which the muscle is stimulated for a firstduration and then the stimulation is turned off for a second durationmay be effective; however, different muscle properties, variations inthe patient condition, and variations in the implant may require adifferent selection of the “on” and “off” periods for each patient andmay also require a change in the initial selection of the “on” and “off”periods over time in the same patient.

In one embodiment, a patient's average functional LES pressure (AP) andminimal functional LES pressure (MP) is set by conducting a parametersetting test, in which a stimulator is controlled by an operator andmanometry measurements of LES and gastric pressures are made. Duringthis test, the operator turns on the stimulation and then observes thefunctional LES pressure while keeping the stimulation on until thefunctional LES pressure crosses a first threshold, defined, for example,by AP+(AP-MP). When the observed pressure passes this first threshold,the stimulation is either turned off or kept on for an additional shortperiod of up to 5 minutes and then turned off. The operator notes thetime when the stimulation is turned off.

The operator continues to observe the pressure and once the pressurereaches MP, the operator turns on the stimulation again and notes thetime. This measurement process continues for several hours, such as 2 to5 hours, so that several stimulation on-off periods can be recorded. Atthe end of the test period, a chronic “on” time is selected to be themedian of the measured “on” periods and a chronic “off” period isselected to be the median of the measured “off” periods. It should beappreciated that the initiation of stimulation, turning off ofstimulation, recordation of time periods, and recordation of functionalLES pressure can be performed automatically, based on a pre-programmedset of threshold values, by a computing device comprising a processorand memory storing the threshold and control instructions as a set ofprogrammatic instructions.

In another embodiment, a patient's average functional LES pressure (AP)and minimal functional LES pressure (MP) is set by conducting aparameter setting test, in which a stimulator is controlled by anoperator and manometry measurements of LES and gastric pressures aremade. During this test, the operator turns on the stimulation, notes theelectrode impedance value, and then observes the functional LES pressurewhile keeping the stimulation on until the pressure crosses a firstthreshold, defined, for example, by AP+(AP-MP). When the observedpressure passes this first threshold, the stimulation is either turnedoff or kept on for an additional short period of up to 5 minutes andthen turned off. The operator notes the time when the stimulation isturned off and the electrode impedance value when the stimulation isturned off.

The operator continues to observe the pressure and once the pressurereaches MP, the operator turns on the stimulation again and notes thetime and electrode impedance value. This measurement process continuesfor several hours, such as 2 to 5 hours, so that several stimulationon-off periods can be recorded. Electrode impedance is measured everytime the stimulation is turned “on” or “off”. At the end of the testperiod, a chronic “on” time is selected to be the median of the measuredimpedance value for the “on” periods and a chronic “off” period isselected to be the median of the measured impedance value for the “off”periods. Rather than setting a stimulation device to operate based onfixed time periods, a stimulation device is programmed to turn off andon based upon the measured impedance values, where the device turns onwhen a patient's impedance value approaches the measured mean, median,or any other calculated impedance value for the on periods and turns offwhen a patient's impedance value approaches the measured median, mean,or any other calculated impedance value for the off periods. It shouldbe appreciated that the initiation of stimulation, turning off ofstimulation, recordation of time periods, recordation of electrodeimpedance, and recordation of functional LES pressure can be performedautomatically, based on a pre-programmed set of threshold values, by acomputing device comprising a processor and memory storing the thresholdand control instructions as a set of programmatic instructions. Itshould be appreciated that, in addition to the above embodiments, apatient's functional LES pressure may be recorded by conducting aparameter setting test, in which a stimulator is controlled by anoperator and manometry measurements of LES and gastric pressures aremade. The recorded functional LES pressures are compared to a predefinedthreshold to determine a maximum pressure which should preferably not beexceeded. The aforementioned on and off periods are then set or modifiedbased on this maximum pressure data.

It should be appreciated that the use of impedance values is useful,relative to manometry measurements, if the values of the “on” and “off”periods in the acute phase do not converge to a small range within a fewminutes. It should further be appreciated that other measurements,instead of impedance, can be used, including physical tension sensors(i.e. implantable strain gauge) or sensors of the muscle electricalactivity or sensor of muscle pressure. Furthermore, it should beappreciated that both of the aforementioned tests can be used, and/orcombined, to fix time windows for the “on” and “off” periods and rely onimpedance measurements in order to adapt, modify, or change the timewindows to account for a possible drift in muscle status

In another embodiment, a doctor makes a determination regarding the LESor fundus electrical stimulation therapy (EST) available to a patient byfirst engaging in a process for evaluating a plurality of appropriatedosing values for a patient. The evaluation process comprises subjectinga patient to a plurality of pulse sequences and measuring thecorresponding LES pressure and gastric pressures.

TABLE 4 Electrical Pulse Pulse Phase # Stimulation Type FrequencyDuration Pulse Amplitude 1 Short Pulse 20 Hz 200 μsec 5 mAmp 2 ShortPulse 20 Hz 200 μsec 3 mAmp If #1 reaches ≥ 20 mmHg 3 Short Pulse 20 Hz200 μsec 7 mAmp If #1 does not reach ≥ 20 mmHg 4 Short Pulse 20 Hz 200μsec 10-15 mAmp If #3 does not reach ≥ 20 mmHg 5 Intermediate 20 Hz 3 ms3-15 mAmp using the same Pulse sequence as 1-4 6 Optimal Pulse 20 HzOptimal Optimal amplitude Pulse

As shown above, each of phases 1-4 is applied for 20-30 minutes with a20-30 minute interval between sessions. The pulse increments can rangefrom 0.1 mAmp to 15 mAmp. The pulse in Phase 6 is intermittently appliedfor 5 hours, during which stimulation is turned on until pressure isgreater than or equal to 20 mmHg for at least 5 minutes (on period) andthen turned off until pressure drops to less than 10 mmHg or patient'sbaseline whichever is higher (off period), and then turned on againuntil it is greater than or equal to 20 mmHg again (on period),repeating thereafter. These on-off sessions continue while the timedurations are recorded. These recorded periods are then used todetermine the optimal duty cycle for the patient during the treatmentphase (patient-specific EST). It should be appreciated that, if asubject experiences pain or discomfort for any given stimulationsequence, the pulse amplitude is decreased in 1 mAmp increments untilstimulation is tolerable. Once the effective tolerable setting isestablished, the patient-specific EST is initiated with the definedstimulation parameters, as determined by the parameter setting stagedescribed above. Preferably, the patient-specific EST is checked at aset schedule (every 6 months or once a year) or when a patient startsreporting GERD symptoms using manometry and the patient-specific ESTparameters are then modified to achieve ideal LES and/or gastricpressures.

It should be appreciated that the aforementioned diagnostic processesaccount for a plurality of variables that substantially affect treatmentquality, treatment efficacy, and patient compliance, including, but notlimited to, patient's disease condition and the correspondingstimulation energy level and frequency required to achieve a positivetherapeutic effect, patient willingness to manually apply stimulation,and form factor of the stimulation source, among other variables.

The variables generated in the course of the diagnostic processes can beused to automatically program a controller, which may be used to controla stimulator. In one embodiment, a diagnostic terminal executing on aconventional computer generates at least one variable, such asstimulation pulse width, frequency, amplitude, ramp rate, or a dutycycle, that substantially affects treatment quality, treatment efficacy,and patient compliance, including, but not limited to, patient's diseasecondition and the corresponding stimulation energy level and frequencyrequired to achieve a positive therapeutic effect, patient willingnessto manually apply stimulation, and form factor of the stimulationsource, among other variables. The diagnostic terminal is in datacommunication with a controller configuration terminal thatelectronically receives a controller into an interface or wirelesslycommunicates with the controller that is responsible for executing thestimulation parameters. Upon generating the variables, the diagnosticterminal transmits the variables, which are eventually received by thecontroller and saved in an appropriate memory location. The controllerthen uses the variables to control one or more stimulation settings.

In another embodiment, the stimulation parameters are checked by aphysician using a data terminal, such as a laptop, tablet computer,mobile device, or personal computer. As discussed above, data relevantto the efficacy of the stimulation parameters can be wirelessly obtainedfrom the stimulation device memory or from a patient controlledcomputing device, such as a tablet computer, laptop, personal computer,or mobile device. The physician can modify the stimulation parameters inaccordance with the received data and, using the data terminal, issuemodified stimulation parameters to the controller of a stimulator asdescribed above.

Exemplary Therapies

The following description is intended to provide examples of how thetherapies, described above, may be specifically implemented. They shouldnot be viewed as limiting the general scope of the inventions describedherein.

Therapy One: Patient Timed and Delivered Stimulation Using A HandheldDevice

In a first therapy, a patient can be effectively therapeutically treatedwith intermittent wireless short bursts of stimulation applied aplurality of times during a day. For example, in one embodiment, apatient can be treated by applying a burst of stimulation for a periodof five minutes or less at a frequency of 5 times or less per day. Inanother embodiment, the stimulation occurs less than 5 times a day for aperiod of 30 minutes or less per stimulation. This stimulation frequencyis effective to treat certain symptoms of a patient, includingdiminishing or eliminating a patient's GERD.

In this treatment method, a patient can be effectively treated by havingthe patient apply an external power source over a predefined area on thepatient's body and manually initiate stimulation. FIG. 16 is oneembodiment of a block diagram of certain modules of a stimulating deviceof the present specification. In one embodiment, the stimulation systemcomprises a stimulation source 1600 and a microstimulator 1601. Thestimulation source 1600 comprises a controller 1602, transducer 1603,waveform generator 1604, and power source 1605, such as a battery. Thestimulation source 1600 directs energy, such as ultrasound or RF energy,across the patient's skin 1610 and toward a microstimulator 1601 that isimplanted directly on the site being stimulated. The stimulation source1600 can generate a plurality of different pulse widths, amplitudes,frequencies, or combinations thereof, as further described below.

In certain situations, the device may require an energy supply to powerthe implantable pulse generator, but it is difficult or undesirable toinclude an implantable battery that would be wired to the device due tosize limitations, restrictions arising from the implant location, or theneed to decrease device costs. In one embodiment, a rechargeable batteryis wired to the stimulator. The rechargeable battery stores a smalleramount of charge, and therefore can be small in size, but is configuredor adapted to be replenished using wireless transmission of energy.

In another embodiment that requires an implanted device size which iseven smaller than that which is possible with a rechargeable battery andassociated recharging circuit, the device comprises a passive circuitthat receives, in real time, transmitted wireless energy from atransmission source external to the patient. The implanted passivecircuit would control the extraction of the transmitted energy and thedelivery of the energy to the rest of the stimulator device. Theexternal energy transmission device would control the timing ofstimulation and any sensing and/or triggering mechanisms relatedthereto. One limitation to the wireless transmission of energy is theamount of energy that can be wirelessly transmitted in any given timedue to, for example, safety or interference requirements. Such wirelessenergy transmission limitations narrow the applicable stimulationamplitude and waveform that can be applied to the tissue, therebylimiting the clinical application and benefit of such systems.

In another embodiment, the microstimulator comprises a means for storinga charge locally, such as a short-term energy storage component or acapacitor, and an associated trigger mechanism. During an on-off dutycycle for stimulating the microstimulator, the off-time of thestimulation duty cycle can be used to temporarily store a charge,thereby enhancing the maximal amplitude and variety of waveform that canbe applied. The implanted device circuit is configured to control andtime the stimulation in response to energy or control information from acontroller that is external to the patient and communicates wirelesslywith the implanted device. The implanted circuit extracts thetransmitted energy or control information and, in response thereto,shapes the waveform within the off-time of each stimulation cycle usingcomponents such as capacitors, diodes, inductors, transistors andresistors.

The operating characteristics of a capacitor integrated with, or localto, the implanted device will be determined, at least in part, by therequired pulse duration and the ratio of required stimulation pulseamplitude to minimal expected extracted supply current within theimplantable device. The capacitor characteristics will also be afunction of the load impedance. For example, assuming a required pulseduration of 200 μs to be applied every 50 ms and a required amplitude of10 mAmp, the device will need to provide a charge of 2 μC (10 mAmp×200μs). Assuming an impedance of 100 ohms with a voltage of 1 V (10mAmp×100 ohm), then the minimum required capacitor will have a value asapproximated by the following equation:

C=Q/V=2uC/1V=2uF

This value will need to be adjusted so that it is not fully dischargedduring stimulation and to compensate for losses within the implantabledevice. For an overall cycle of, for example, 50 ms, the theoreticalminimal extracted supply current that can drive the required pulse willbe:

Minimal extracted current=10 mAmp×200 μs/(50 ms−200 μs)=0.04 mAmp

Adjusting for internal losses within the stimulator will yield apractical limit of about 0.1 mAmp or 100 μAmp. Higher available supplycurrents can allow for shorter cycles or longer pulse duration asnecessary and can be extrapolated from the above.

In one embodiment, energy need not be stored between cycles and thepassive circuit responds, in real-time, to the wireless transmission ofenergy. For example, the implanted circuit may initiate a stimulationpulse in response to a stimulation pulse wirelessly sent by the externalenergy transmitting unit, where the energy transmission is above apre-defined time period, is characterized by the intermittent ceasing ofenergy transmission, or is characterized by another combination of“on”-“off” energy signals.

In one embodiment, the stimulation source 1600 directs ultrasonic energyto the microstimulator 1601 which comprises an ultrasonic receiver. Themicrostimulator 1601 is implanted into the area to be stimulated via anendoscope. The microstimulator 1601 can function either as apass-through for energy and stimulation parameters or comprise an energystorage and programmatic memory to deliver short stimulation bursts,using the stored energy, at predetermined time intervals, pursuant tothe programmed memory.

In one embodiment, the stimulation source 1600 directs radio frequency(RF) energy to the microstimulator 1601 which comprises an RF receiver.The microstimulator 1601 is implanted into the area to be stimulated viaan endoscope. The microstimulator 1601 can function either as apass-through for energy and stimulation parameters or comprise an energystorage and programmatic memory to deliver short stimulation bursts,using the stored energy, at predetermined time intervals, pursuant tothe programmed memory.

In one embodiment, the stimulation source 1600 comprises a controller1602, transducer 1603, waveform generator 1604, and power source 1605,such as a battery. Operationally, the controller 1602, via a processorin data communication with a memory storing programmatic instructions,causes the waveform generator 1604 to generate a predefined waveform,having an associated pulse width, amplitude, and frequency, which istransmitted via the transducer 1603 to the endoscopically implantedmicrostimulator 1601. A patient applies the stimulation source 1600intermittently for a short time period, preferably 30 minutes or less,over the microstimulator 1601 site. Where the microstimulator 1601comprises a local memory for storing programmatic instructions, inparticular stimulation parameters and processes, the stimulation source1600 need not comprise a controller and memory for storing suchprogrammatic instructions and may simply transmit a predefined amount ofenergy to the microstimulator.

In another embodiment, referring to FIG. 17 , the stimulation source1700 comprises a controller 1702, waveform generator 1704, and powersource 1705, such as a battery. It wirelessly communicates with, and/ortransfers energy to, a transducer 1703 that is implanted subcutaneously.The subcutaneous transducer 1703 receives the wirelessly transmittedenergy, such as RF or ultrasound, through the patient's skin surface andtransmits it, via a wired or wireless connection, to an endoscopicallyimplanted microstimulator 1701. Operationally, the controller 1702, viaa processor in data communication with a memory storing programmaticinstructions, causes the waveform generator 1704 to generate apredefined waveform, having an associated pulse width, amplitude, andfrequency, which is transmitted wirelessly into the patient'ssubcutaneous region and into the transducer 1703, which furthertransmits the energy to the microstimulator 1701. A patient applies thestimulation source 1700 intermittently for a short time period,preferably thirty minutes or less, over the transducer site. Where themicrostimulator 1701 comprises a local memory for storing programmaticinstructions, in particular stimulation parameters and processes, thestimulation source 1700 need not comprise a controller and memory forstoring such programmatic instructions and may simply transmit apredefined amount of energy to the transducer 1703 and, thus, to themicrostimulator 1701. It should be appreciated that, regardless of thetype, the stimulation source 1700 can be integrated into a plurality ofdifferent housings, including a miniature flashlight, cell phone case,or smart card. In one embodiment, the subcutaneous transducer 1703receives lower frequency electro-magnetic energy and commands from thestimulation source 1700 and converts the energy into high frequency RFenergy. The frequency conversion will be less efficient than direct RFtransmission but the use of the subcutaneous transducer will assist ineliminating heating issues. In addition, the subcutaneous transducer canalso be used as a simple energy storage unit. In another embodiment, thesubcutaneous transducer 1703 receives lower frequency electro-magneticenergy and commands from the stimulation source 1700 and converts theenergy into ultrasound energy.

In another embodiment, referring to FIG. 18 , a patient is treated bylaparoscopically implanting a plurality of electrodes 1801 (within theanatomical area to be stimulated) in wired communication with atransducer 1803 (comprising an antenna) proximate the skin surface. Thetransducer 1803 wirelessly communicates with an external energy source1800 (comprising a controller 1802, waveform generator 1804, and powersource 1805, such as a battery) across the surface of the patient's skin1810. The external energy source 1800 can be applied to the stimulationsite by a patient, as described above. With close energy sourceapplication, radio frequency, ultrasound, or inductive/magnetic energiescan be used.

Referring to FIGS. 16-18 simultaneously, as further discussed below, thestimulation source 1600, 1700, 1800 can initiate or terminatestimulation, when properly placed over the appropriate site, based onany of a plurality of triggers, including manually by a patient, patientactivity, or other sensed patient states. The stimulation source 1600,1700, 1800 can generate a plurality of different pulse widths,amplitudes, frequencies, or combinations thereof, as further describedbelow.

Therapy Two: Controller Timed and Delivered Stimulation

In a second therapy, a patient may not be effectively therapeuticallytreated with intermittent wireless short bursts of stimulation applied aplurality of times during a day. Rather, a patient requires bursts ofstimulation for a period greater than a predefined period of time, orfor a frequency of more than a predefined number of times per day.Accordingly, a patient is subjected to stimulation that is initiated,effectuated, or otherwise triggered by a programmed controller. Thismore frequent, or continuous, stimulation is effective to treat certainsymptoms of a patient, including treatment of GERD, or reaching apredetermined LES high pressure zone length, gastric pressure, LESpressure, muscle tension or electrode impedance.

In this treatment method, a patient can be effectively treated by aplurality of embodiments, including:

1) Referring to FIG. 19 , endoscopically implanting a microstimulator1901 (having a receiver and placed within the anatomical area to bestimulated) in wireless or wired communication with a subcutaneouslyimplanted transducer 1903 that, in turn, wirelessly communicates with atransducer 1906 (comprising at least one antenna and an adhesivesurface) applied to the patient's skin surface 1910 which is wired to,and receives signals from, a stimulator source 1900 (comprising acontroller 1902, waveform generator 1904, and power source 1905, such asa battery). The controller 1902 can be programmed to initiate orterminate stimulation based on a plurality of patient-specific triggers,such as pH level, LES high pressure zone length, gastric pressure, LESpressure, fasting state, eating state, sleeping state, physical incline,or patient activity state, among other triggers as further describedbelow. The stimulation source 1900 can generate and transmit radiofrequency or ultrasound energy and can generate a plurality of differentpulse widths, amplitudes, frequencies, or combinations thereof, asfurther described below. In one embodiment, the radio frequency orultrasound pulse is designed to operate over a wireless distance of 6inches or less, through the human body, with a maximum pulse amplitudeof 10 mAmp and a maximum pulse width of 10 msec. It should beappreciated that if one parameter is lowered, such as the wirelessdistance (lowering it to one inch), another parameter can be modifiedaccordingly, such as the amplitude (increasing it to 30 mAmp).

2) Referring to FIG. 20 , endoscopically implanting a microstimulator2001 (having a receiver and placed within the anatomical area to bestimulated) in wireless communication with a stimulator source 2000(comprising a controller 2002, transducer 2003, waveform generator 2004,and power source 2005, such as a battery) and which is held against apatient's skin 2010 over the microstimulator site with straps,adhesives, garments, or bindings. The controller 2002 can be programmedto initiate or terminate stimulation based on a plurality ofpatient-specific triggers, such as pH level, LES pressure, fastingstate, eating state, sleeping state, physical incline, or patientactivity state, among other triggers as further described below. Thestimulation source 2000 can generate and transmit radio frequency orultrasound energy and can generate a plurality of different pulsewidths, amplitudes, frequencies, or combinations thereof, as furtherdescribed below. In one embodiment, the radio frequency or ultrasoundpulse is designed to operate over a wireless distance of 6 inches orless, through the human body, with a maximum pulse amplitude of 10 mAmpand a maximum pulse width of 10 msec. It should be appreciated that ifone parameter is lowered, such as the wireless distance (lowering it toone inch), another parameter can be modified accordingly, such as theamplitude (increasing it to 30 mAmp).

3) Referring to FIG. 21 , endoscopically implanting a microstimulator2101 (having a receiver and placed within the anatomical area to bestimulated) in wireless communication with a relay device 2106 worn overthe stimulation site 2110 that is in wired communication with anexternal stimulator 2100, The external stimulator 2100 is in wirelesscommunication with an implanted adapter 2107, which is in wirelesscommunication with an external stimulator 2100, or in wirelesscommunication with an implanted transducer 2108 that is in wiredcommunication, via an electrode, to an implanted stimulator 2109. Thestimulator 2100 (comprising a controller 2102, transducer 2103, waveformgenerator 2104, and power source 2105, such as a battery) can beprogrammed to initiate or terminate stimulation based on a plurality ofpatient-specific triggers, such as pH level, LES high pressure zonelength, gastric pressure, LES pressure, fasting state, eating state,sleeping state, physical incline, or patient activity state, among othertriggers as further described below. The stimulation source 2100 cangenerate and transmit radio frequency or ultrasound energy and cangenerate a plurality of different pulse widths, amplitudes, frequencies,or combinations thereof, as further described below. In one embodiment,the radio frequency or ultrasound pulse is designed to operate over awireless distance of 6 inches or less, through the human body, with amaximum pulse amplitude of 10 mAmp and a maximum pulse width of 10 msec.It should be appreciated that if one parameter is lowered, such as thewireless distance (lowering it to one inch), another parameter can bemodified accordingly, such as the amplitude (increasing it to 30 mAmp).

4) Referring to FIG. 22 , laparoscopically implanting a plurality ofelectrodes 2201 (within the anatomical area to be stimulated) in wiredcommunication with an implanted stimulator 2200 (comprising a primarycell that provides energy and a memory with programmatic instructionsfor defining appropriate stimulation parameters) which can be programmedto generate stimulation either continuously or periodically based on apredefined program or based on patient-specific triggers, such as pHlevel, LES high pressure zone length, gastric pressure, LES pressure,LES impedance, fasting state, eating state, sleeping state, physicalincline, or patient activity state, among other triggers as furtherdescribed below. In one embodiment, the stimulator 2200 wirelesslyreceives control data or information from an external device, which iscontrolled, at least in part, by a physician or patient. The stimulator2200 can generate a plurality of different pulse widths, amplitudes,frequencies, or combinations thereof, as described above.

5) Referring to FIG. 23 , laparoscopically implanting a plurality ofelectrodes 2301 (within the anatomical area to be stimulated) in wiredcommunication with a subcutaneously implanted transducer 2302 that, inturn, wirelessly communicates with a stimulator source or a transducer2303 (comprising at least one antenna and an adhesive surface) appliedto the patient's skin surface 2310 which is wired to, and receivessignals from, a stimulator source 2300 (comprising a controller 2304,waveform generator 2305, and power source 2306, such as a battery). Thecontroller 2304 can be programmed to initiate or terminate stimulationbased on a plurality of patient-specific triggers, such as pH level, LEShigh pressure zone length, gastric pressure, LES pressure, fastingstate, eating state, sleeping state, physical incline, or patientactivity state, among other triggers as further described below. Thestimulation source 2300 can generate and transmit radio frequency orultrasound energy and can generate a plurality of different pulsewidths, amplitudes, frequencies, or combinations thereof, as furtherdescribed below.

It should be appreciated that, while the disclosed system can use RF,inductive coupling, magnetic coupling or ultrasound, in one embodiment,the system can combine the use of RF inductive coupling, magneticcoupling, and ultrasound to take best advantage of transmissionefficiencies in various media. In one embodiment, the externalstimulator source generates RF waveforms, which wirelessly transmit RFenergy to an intermediary receiver that can be implanted subcutaneouslyand that converts the received RF energy into an ultrasound waveform.The intermediary receiver has an RF receiver, an ultrasound waveformgenerator, and an ultrasound transmitter. In another embodiment, thedevice comprises a means for storing a charge locally, such as ashort-term energy storage component (capacitor), and an associatedtrigger mechanism, as described above.

It should further be appreciated that the microstimulator (or, where alaparoscopically implanted stimulation electrode and stimulator areused, the stimulator) can locally store energy, be used with RF or US,and rely on an external device for stimulation control and/or energyrecharge. Specifically, the microstimulator can comprise a means forstoring a charge locally, such as a capacitor. It should further beappreciated that the anatomical region to be stimulated, such as theLES, areas within 2 cm of the LES, the esophagus, or the UES, may bestimulated using a plurality of microstimulators or electrodes,including an array of microstimulators or electrodes affixed to a meshor other substrate. It should further be appreciated the microstimulatoror implanted stimulator can store enough energy to function as a backup,or otherwise fill in gaps in energy transfer from an external sourcewhen, for example, wireless transmission coupling is interrupted orinefficient. In another embodiment, the microstimulator or implantedstimulator receives an energy stream from an external stimulator and, inreal-time, forms the requisite waveform based on parameters encoded in awireless control stream or embedded in the energy stream. In anotherembodiment, the microstimulator or implanted stimulator receives apre-formed waveform from an external stimulator.

As discussed above, the endoscopic therapeutic treatments are part ofthe diagnosis process in which a microstimulator is endoscopicallyimplanted and used in combination with an external device for an initialperiod. Data is gathered regarding frequency of stimulation required,amount of energy required, and other factors. A patient then receives alaparoscopically implanted permanent system operating in accordance withthe gathered data.

Exemplary Use No. 1

In one embodiment, patients with diagnosis of GERD responsive to PPI,increase esophageal acid on 24 h pH monitoring off GERD medications,basal LES pressures ≥5 mm Hg, hiatal hernia <2 cm and esophagitis ≤LAGrade B had a stimulator placed endoscopically in the LES by creating a3 cm submucosal tunnel. The stimulator was secured to the esophagusmuscularis or serosa. Electrical stimulation (EST) was delivered 6-12hours post-implant per following protocols 1) Short-pulse (SP) 200 μsec,20 Hz, 10 mAmp; if no response in LES pressure increase to 15 mAmp; ifincrease in LES pressure decrease to 5 mAmp and 2) Intermediate-pulse(IP) 3 msec, 20 Hz, 5 mAmp for 20 minutes; if no response, increase to10 mAmp. Each session of EST lasted 20 minutes and was followed by awashout period of 20 minutes or time needed for LES pressure to returnto baseline, whichever was longer. High-resolution manometry wasperformed using standard protocol pre-, during and post-stimulation.Symptoms of heartburn, chest pain, abdominal pain and dysphagia pre-,during and post-stimulation were also recorded. Continuous cardiacmonitoring was performed during and after the stimulation to look forany adverse cardiac events associated with EST.

Three patients underwent successful stimulator implantation. One patientwas stimulated using 200 μsec, 20 Hz, 3 mAmp (SP 3) and had asignificant increase in the LES pressure (Baseline=5.7 mm Hg;post-stimulation=42 mm Hg). As shown in FIGS. 24-30 , patients had asignificant increase in the LES pressure with all sessions of EST (Table5). There was no effect on swallow induced relaxation and improvement inpost-swallowing LES pressure augmentation with EST. There were noadverse EST related symptoms or any cardiac rhythm abnormalities.

TABLE 5 EST Protocol Median LES pressure (mmHg) Pre- Post- StimulationStimulation Stimulation SP-10 mAmp 8.1 25.3 17.9 SP-5 mAmp 9.7 37.7 17.8IP-5 mAmp 6.5 26.0 29.2

Accordingly, in patients with GERD, EST results in significant increasein LES pressure without affecting patient swallow function or inducingany adverse symptoms or cardiac rhythm disturbances. EST delivered via awired or wireless electrical stimulator offers a novel therapy topatients with GERD.

Exemplary Use No. 2

In one embodiment, a patient with diagnosis of GERD has a baseline LESpressure of 4-6 mmHg and impedance was about 320 ohms. A stimulationhaving a pulse of 200 μs and 5 mAmp was applied. After 15 minutes, asustained LES tone of 25-35 mmHg was observed, which remained high forover 90 minutes after stopping stimulation. After 3 hours, the LESpressure returned to baseline. This patient was than treated using apatient specific stimulation protocol of 200 μs pulse, 5 mAmp amplitude,20 Hz frequency, an ON phase of 20 minutes and an OFF phase of 2 hours.His LES was restored to normal function and his GERD was controlled.

Exemplary Use No. 3

In one embodiment, a patient with diagnosis of GERD has a baseline LESpressure of 4-6 mmHg and impedance was about 320 ohms. A stimulationhaving a pulse of 200 μs and 10 mAmp was applied. After 15 minutes, asustained LES tone of 25-35 mmHg was observed. The patient wasinstructed to engage in a wet swallow. The patient engaged in a wetswallow, while stimulation was being applied, without feeling anysubstantive inhibition of the swallow function. This patient was thentreated using a patient specific stimulation protocol of 200 μs pulse, 5mAmp amplitude, 20 Hz frequency, an ON phase of 20 minutes and an OFFphase of 2 hours. His LES was restored to normal function and his GERDwas controlled. Optionally, a pressure sensor was implanted in the LESand used to terminate the ON phase when a sustained LES pressure ofgreater than 20 mmHg for 5 minutes was achieved and used to terminatethe OFF phase when a sustained LES pressure reaching 10 mmHg or thepatient's baseline, whichever is higher, was achieved.

Exemplary Use No. 4

In one embodiment, patients are subjected to a series of diagnostictests to determine a plurality of therapeutic stimulation parameters andto select stimulation parameters with the lowest average charge which isstill able to elicit a pressure response in the range of at least 15-20mmHg sustained for at least 5 minutes as measured in manometry. Thediagnostic tests include subjecting patients to a series of stimulationsequences, as provided in the table below:

TABLE 6 Stimulation Sequence Settings Electrical Stimulation Pulse PulseSequence # Type Frequency Duration Pulse Amplitude 1 High-Frequency 20Hz 200 μsec 5 mAmp 2 (only if #1 does High-Frequency 20 Hz 200 μsec10-15 mAmp (preferably not reach 20 10 mAmp) mmHg or invoke asufficiently positive response) 3 (only if #2 does Mid-Frequency 20 Hz 3ms 5-15 mAmp (preferably not reach 20 10 mAmp) mmHg or invoke asufficiently positive response) 4 (only if #3 does Mid-Frequency 20 Hz 3ms 5-15 mAmp not reach 20 mmHg or invoke a sufficiently positiveresponse) 5 (only if #4 does Low-frequency 6 375 ms 5 mAmp not reach 20cycles/min mmHg or invoke a sufficiently positive response) 6 (only if#5 does Low-frequency 6 375 ms 5-15 mAmp not reach 20 cycles/min mmHg)

Each selected stimulation parameter is applied for 5 hours during whichstimulation is turned on until pressure is greater than or equal to 20mmHg for at least 5 minutes (or until the time of duration reaches 60minutes) and then stimulation is turned off until the pressure drops toless than 10 mmHg, or the patient's baseline, whichever is higher.Stimulation is then turned on again until reaching greater than or equalto 20 mmHg again for at least 5 minutes. This on-off process continueswhile the time duration between each on-off cycle is recorded. If thepatient experiences pain or discomfort for any given stimulationsequence, the pulse amplitude is decreased in 1 mAmp increments untilstimulation is tolerable. Once the tolerable setting is established, thestimulation period is re-initiated. Optionally, there is a washoutperiod between sequences to remove any residual effect from theapplication of a prior sequence. That washout period can be equal to onehour or until LES pressure returns to the patient's baseline, whicheveris longer. Optionally, continuous manometry is performed during thepost-stimulation period to assess any delayed effect from a failedsequence or to measure the duration of effect from a successfulsequence.

During the last two hours of the diagnostic session, stimulation isturned “on” and “off” at fixed durations based on the measured valuesrecorded in the first part of the test. Impedance measurements areperformed periodically during this phase using an external impedancemeasurement device or by measuring the resulting voltage waveform fromstimulation using a floating oscilloscope.

Optionally, a second dosing evaluation process is performed building onthe sequence results as performed above. In one embodiment, a patient'sbaseline LES pressure is evaluated over a 20 minute period. Simulationis applied for 125% of the on time period, as determined from the firstset of sequence measurements. Stimulation is then stopped for 75% of theoff time period, as determined from the first set of sequencemeasurements, or until LES pressure falls below 10 mmHg or baseline,whichever is higher. Restart stimulation for 125% of the on time periodand monitor LES pressure. If LES pressure does not reach 20 mmHg, thencontinue stimulation for up to 150% of the on time period or untilpressure reaches 20 mmHg (whichever comes first). Repeat the off timeperiod and continue cycling between the prior on time period and offtime period until achieving 6 hours of LES pressure above 10 mmHg.Conduct esophageal manometry with wet swallows post stimulationsequence.

Exemplary Use No. 5

In one embodiment, patients are subjected to a series of diagnostictests to determine a plurality of therapeutic stimulation parameters andto select stimulation parameters with the lowest average charge which isstill able to elicit a pressure response in the range of at least 15-20mmHg sustained for at least 5 minutes as measured in manometry. Thediagnostic tests include subjecting patients to a series of stimulationsequences, as provided in the table below:

TABLE 7 Electrical Stimulation Pulse Pulse Pulse Stimulation Sequence #Type Frequency Duration Amplitude Duration 1 Baseline  0 Hz  0 μsec 0mAmp  0 minutes 2 High-Frequency 20 Hz 200 μsec 5 mAmp 30 minutes 3(only if #2 does High-Frequency 20 Hz 200 μsec 10-15 60 minutes notreach 20 mAmp mmHg or invoke a (preferably sufficiently 5 mAmp) positiveresponse) 4 (only if #3 does High-Frequency 20 Hz 200 μsec 10 mAmp 30minutes not reach 20 mmHg or invoke a sufficiently positive response) 5(only if #4 does High-Frequency 20 Hz 200 μsec 5-15 mAmp 60 minutes notreach 20 (preferably mmHg or invoke a 10 mAmp) sufficiently positiveresponse) 6 (only if #5 does High-Frequency 20 Hz 200 μsec 15 mAmp 30minutes not reach 20 mmHg or invoke a sufficiently positive response) 7(only if #6 does High-Frequency 20 Hz 200 μsec 15 mAmp 60 minutes notreach 20 mmHg)

Stimulation is turned on until pressure is greater than or equal to 20mmHg for at least 5 minutes (or until the list time duration is reached)and then stimulation is turned off until the pressure drops to less than10 mmHg, or the patient's baseline, whichever is higher. Stimulation isthen turned on again until reaching greater than or equal to 20 mmHgagain for at least 5 minutes. This on-off process continues while thetime duration between each on-off cycle is recorded. If the patientexperiences pain or discomfort for any given stimulation sequence, thepulse amplitude is decreased in 1 mAmp increments until stimulation istolerable. Once the tolerable setting is established, the stimulationperiod is re-initiated.

Optionally, there is a washout period between sequences to remove anyresidual effect from the application of a prior sequence. That washoutperiod can be equal to one hour or until LES pressure returns to thepatient's baseline, whichever is longer. Optionally, continuousmanometry is performed during the post-stimulation period to assess anydelayed effect from a failed sequence or to measure the duration ofeffect from a successful sequence. Optionally, continuous manometry isperformed during the post-stimulation period from the successfulsequence to determine the duration of the effect, that is, until the LESpressure is below 10 mm Hg or reaches baseline, whichever is higher.

The stimulation sequences listed above may be repeated, if no success isachieved, except using a 3 msec dose instead of the 200 μsec dose.

Optionally, a second dosing evaluation process is performed building onthe sequence results as performed above. In one embodiment, a patient'sbaseline LES pressure is evaluated over a 20 minute period. Simulationis applied for 125% of the on time period, as determined from the firstset of sequence measurements. Stimulation is then stopped for 75% of theoff time period, as determined from the first set of sequencemeasurements, or until LES pressure falls below 10 mmHg or baseline,whichever is higher. Stimulation is restarted for 125% of the on timeperiod and LES pressure is monitored. If LES pressure does not reach 20mmHg, then continue stimulation for up to 150% of the on time period oruntil pressure reaches 20 mmHg (whichever comes first). Repeat the offtime period and continue cycling between the prior on time period andoff time period until achieving 6 hours of LES pressure above 10 mmHg.Conduct esophageal manometry with wet swallows post stimulationsequence. Additional stimulation measurements can be made, includingbaseline manometry with wet swallows, repeating successful sequences foran extended period, such as 12 hours, or manometry measurements with wetswallows after conducting a successful stimulation sequence.

Exemplary Use No. 6

In one embodiment, 10 patients (9 females, 1 male mean age 52.6 years,range-40-60 years) with symptoms of GERD responsive to PPI's, lowresting LES pressure and abnormal 24-hr intraesophageal pH test wereenrolled. All had symptoms of heartburn and/or regurgitation for atleast 3 months, which was responsive to therapy with proton pumpinhibitors (PPI's). Preoperative evaluation included an upper GIendoscopy, esophageal manometry and ambulatory 24-hr esophageal pHrecording. To be included, the patient's resting LESP had to be 5-15mmHg, and the intraesophageal pH had to be less than four more than 5%of the time. Patients with hiatal hernia >3 cm, erosive esophagitis moresevere than Los Angeles grade C, Barrett's esophagus or non-GERD relatedesophageal disease were excluded.

Bipolar stitch electrodes were placed longitudinally in the LES duringan elective laparoscopic surgery, secured by a clip and exteriorizedthrough the abdominal wall. It consisted of two platinum-iridiumelectrodes with an exposed length of 10 mm. They were implantedlongitudinally in the right and left lateral aspects the LES and securedby a clip. The electrode was then exteriorized through the laparoscopicport in the abdominal wall in the left upper quadrant and connected to amacro stimulator.

Following recovery, an external pulse generator delivered 2 types ofstimulation for periods of 30 minutes: 1) low energy stimulation; pulsewidth of 200 μsec, frequency of 20 Hz amplitude and current of 5 to 15mA (current was increased up to 15 mA if LESP was less than 15 mmHg),and 2) high energy stimulation; pulse width of 375 msec, frequency of 6cpm and amplitude 5 mA. Resting LESP, amplitude of esophagealcontractions and residual LESP in response to swallows were assessedbefore and after stimulation. Symptoms of chest pain, abdominal pain anddysphagia were recorded before, during and after stimulation and 7-daysafter stimulation. Continuous cardiac monitoring was performed duringand after stimulation.

The high frequency, low energy stimulation was delivered as square-wavepulses with a width of 200 microseconds at a frequency of 20 Hz and acurrent of 5-15 mA. If LESP did not increase to over 15 mmHg using the 5mA stimulus, the current was gradually increased up to 15 mA. The lowfrequency, high energy stimulation was delivered as square-wave pulsewith a width of 375 milliseconds at a frequency of 6 CPM and current of5 mA. The current was not varied during low frequency stimulation.

If resting LESP rose above 15 mmHg during ES, the stimulus wasterminated and LESP was allowed to return to its pre-stimulationbaseline. A different stimulation was given when LESP returned tobaseline. Stimulations were given in random order, with patients unawareof the type or timing of its delivery (frequent checks of impedance weremixed with stimulation). Five water swallows were given before and aftertermination of each session of ES. All studies were done undercontinuous cardiac monitoring, and patients were supervised closely.Patients were instructed to report any unusual symptom, and inparticular dysphagia, palpitations, and chest/abdominal pain.

Nine subjects received high frequency, low energy and four subjectsreceived low frequency, high energy stimulation. Both types ofstimulation significantly increased resting LESP: from 8.6 mmHg 95%, CI4.1-13.1 to 16.6 mmHg, 95% CI 10.8-19.2, p<0.001 with low energystimulation and from 9.2 mmHg 95% CI 2.0-16.3 to 16.5 mmHg, 95% CI2.7-30.1, p=0.03 with high energy stimulation. Neither type ofstimulation affected the amplitude of esophageal peristalsis or residualLESP. No subject complained of dysphagia. One subject had retrosternaldiscomfort with stimulation at 15 mA that was not experienced withstimulation at 13 mA. There were no adverse events or any cardiac rhythmabnormalities with either type of stimulation.

With respect to high frequency, low energy stimulation, there was aconsistent increase in resting LESP in all subjects, observed within 15minutes of initiating ES, and increased further before the end ofstimulation. High frequency, low energy stimulation had no effect on theamplitudes of esophageal contractions or residual LESP in response to 5cc water swallows. One subject had chest discomfort when the stimulationcurrent was increased to 15 mA, but resolved when the current wasdecreases to 13 mA.

With respect to low frequency, high energy stimulation, resting LESPconsistently increased during stimulation. It had no effect on theamplitudes of peristaltic pressure waves in the smooth muscle esophagusor residual LESP produced by 5 cc water swallows. No abnormalities ofcardiac or esophageal function were seen, and no adverse events occurredwith either type of stimulation.

Both types of stimulation, high and low energy stimulation, caused aconsistent and significant increase in LES pressure. Importantly, bothLES relaxation and esophageal contractile activity in response to wetswallows were not affected, indicating that the integrity of theneuromuscular reflex pathways activated by swallows is maintained duringstimulation. Stimulation was well tolerated. No patient reporteddysphagia. Only one patient reported chest discomfort, with amplitude of15 mA, that was not experienced when current was reduced to 13 mA. Therewas no evidence of cardiac adverse effects in any of the patients.Accordingly, short-term stimulation of the LES in patients with GERDsignificantly increases resting LESP without affecting esophagealperistalsis or LES relaxation.

Exemplary Use No. 7

Six patients with GERD resistant to medical therapy and documented by pHtesting underwent electrode implantation in the LES using laparoscopy.All patients had LES pressures in the range of 5-15 mm Hg. Amacrostimulator was placed in the subcutaneous pocket using steriletechniques. Within 24 hours after the implant, LES electricalstimulation therapy was started using 215 μsec pulse at 3 mAmp and 20Hz. For certain patients, the macrostimulator comprised anaccelerometer/inclinometer which was used to program the delivery ofstimulation twice daily, once every 12 hours, and then increased to 3times daily, once every 8 hours.

The LES electrical stimulation therapy resulted in significantimprovement and normalization of LES pressure as measured byhigh-resolution manometry and clinically significant decreases inesophageal acid as measured by 24 hour pH testing. All patients haddecreases in symptoms measured by patient symptom diaries andimprovements in health related quality of life measured by a HealthRelated Quality of Life survey, short form 12 (GERD HRQL). All patientswere successfully taken off proton pump inhibitors medications, nor didthe patients use the PPIs on an as-needed basis. None of the patientshad treatment related symptoms or adverse events. All patientsmaintained a normal swallow function.

Referring to FIGS. 24 to 30 , the treatment methodologies disclosedherein provide for a sustained improvement in patient LES pressure, adecrease in esophageal acid exposure, and decrease in reported symptoms.Referring to FIG. 24 , using a short pulse, relative to a baselinepressure 2410, patient LES pressure can achieve a greater than 2 timesincrease during stimulation 2415 relative to baseline 2410 and can stillretain an elevated pressure, relative to baseline 2410, afterstimulation is terminated 2420.

Additionally, as shown in FIGS. 25 and 26 , using a short orintermediate pulse, a patient's LES pressure can be reliably maintainedwithin or above a normal pressure range, 15-25 mmHg 2505, 2605, forweeks after LES stimulation is initiated. As a result, a patient'sesophageal acid exposure can be brought within a normal pH range withinone week after initiating treatment and maintained for several weeksthereafter. Similarly, a patient's adverse symptoms, associated withGERD, can be brought within a normal range, as measured by GERD HRQLevaluations, within one week after initiating treatment and maintainedfor several weeks thereafter. The benefits of the present therapy canalso be obtained within hours after initiating and terminatingstimulation. As shown in FIGS. 27, 28, and 29 , relative to apre-stimulation LES pressure profile 2705, a greater LES pressureprofile 2805 can be attained during stimulation and an improved LESpressure profile 2905 can be reliably maintained for hours after LESstimulation is terminated. FIG. 30 is another graph showing an improvedLES pressure profile over time. LES pressure increases 3010 over abaseline pressure 3015 and remains elevated 3520 after stimulation isterminated.

The above examples are merely illustrative of the many applications ofthe system of the present invention. Although only a few embodiments ofthe present invention have been described herein, it should beunderstood that the present invention might be embodied in many otherspecific forms without departing from the spirit or scope of theinvention. Therefore, the present examples and embodiments are to beconsidered as illustrative and not restrictive, and the invention may bemodified within the scope of the appended claims.

We claim:
 1. A system for increasing a length of a high pressure zone ofa lower esophageal sphincter (LES) of a patient, said system comprising:at least one electrically stimulating electrode positioned proximatesaid LES; a waveform generator coupled to said at least one electrode;and, a controller configured to electrically stimulate an area proximatesaid LES to increase the length of said high pressure zone above athreshold level which reduces at least one of a frequency of occurrenceor an intensity of gastroesophageal reflux symptoms in said patient. 2.The system of claim 1, wherein said at least one electrode is positionedwithin said LES.
 3. The system of claim 1, wherein said at least oneelectrode is positioned within a gastric cardia of said patient.
 4. Thesystem of claim 1, wherein said at least one electrode is positioned inan area within 3 cm of said LES.
 5. The system of claim 1, comprising atleast two electrodes wherein at least one first electrode is positionedwithin said LES and at least one second electrode is positioned within agastric cardia of said patient.
 6. The system of claim 1, comprising atleast two electrodes wherein at least one first electrode is positionedwithin said LES and at least one second electrode is positioned in anarea within 3 cm of said LES.
 7. The system of claim 1, comprising atleast two electrodes wherein at least one first electrode is positionedwithin a gastric cardia of said patient and at least one secondelectrode is positioned in an area within 3 cm of said LES.
 8. Thesystem of claim 1, comprising at least three electrodes wherein at leastone first electrode is positioned within said LES, at least one secondelectrode is positioned within a gastric cardia of said patient, and atleast one third electrode is positioned in an area within 3 cm of saidLES.
 9. The system of claim 1, wherein said high pressure zone has abaseline length prior to stimulation and said threshold level defines alength of said high pressure zone which is at least 10% greater thansaid baseline length.
 10. A system for increasing a length of a highpressure zone of a lower esophageal sphincter (LES) of a patient, saidsystem comprising: at least one electrically stimulating electrodepositioned proximate said LES; a waveform generator coupled to said atleast one electrode; a controller configured to electrically stimulatean area proximate said LES to increase the length of said high pressurezone above a threshold level which reduces at least one of a frequencyof occurrence or an intensity of gastroesophageal reflux symptoms insaid patient; wherein an average pressure within said high pressure zoneis greater than 5 mm Hg and wherein said high pressure zone has abaseline length prior to stimulation and said threshold level defines alength of said high pressure zone which is at least 10% greater thansaid baseline length.
 11. The system of claim 10, wherein said at leastone electrode is positioned within said LES.
 12. The system of claim 10,wherein said at least one electrode is positioned within a gastriccardia of said patient or within 3 cm of said LES.
 13. The system ofclaim 10, further comprising at least one sensor for sensing at leastone physiological parameter of said patient.
 14. The system of claim 13,wherein said at least one sensor is configured to measure any one orcombination of LES high pressure zone length, LES pressure, esophagealpH, inclinometer data, temperature, or accelerometer data.
 15. Thesystem of claim 14, wherein said controller is configured toelectrically stimulate said area proximate said LES based on data sensedby said at least one sensor.
 16. A method for increasing the length of ahigh pressure zone of a lower esophageal sphincter (LES) of a patient,said method comprising the steps of: providing an electrical stimulationsystem, said system comprising: at least one electrically stimulatingelectrode; a waveform generator coupled to said at least one electrode;and, a controller configured to operate said waveform generator totransmit an electrical current to said at least one electrode;implanting said at least one electrode within 3 cm of said LES or withina gastric cardia of said patient; and, operating said controller tocause said at least one electrode to electrically stimulate an areaproximate said LES to increase the length of said high pressure zoneabove a threshold level which reduces at least one of a frequency ofoccurrence or an intensity of gastroesophageal reflux symptoms in saidpatient.
 17. The method of claim 16, wherein said at least one electrodeis positioned within said LES.
 18. The method of claim 16, wherein anaverage pressure within said high pressure zone is greater than 5 mm Hg.19. The method of claim 16, wherein said high pressure zone has abaseline length prior to stimulation and said threshold level defines alength of said high pressure zone which is at least 10% greater thansaid baseline length.
 20. The method of claim 16, wherein saidelectrical stimulation system further comprises at least one sensor,said method further comprising the steps of: sensing at least onephysiological parameter of said patient via said at least one sensor;and, modifying the operation of said controller to cause said at leastone electrode to electrically stimulate an area proximate said LES basedupon said at least one sensed physiological parameter.